JP5470043B2 - Benzoxazinone derivatives - Google Patents

Description

  The benzoxazinone derivative of the present invention is a long-chain fatty acid elongation enzyme (hereinafter sometimes abbreviated as LCE) inhibitor, and is used as various cardiovascular diseases, nervous system diseases, metabolic diseases, It is useful as a treatment for reproductive and gastrointestinal diseases.

  Fatty acid biosynthesis is performed by acetyl CoA carboxylase and fatty acid synthase. LCE is a type of fatty acid synthase, and in the fatty acid synthesis pathway where synthesis starts with acetyl CoA as a substrate, lauric acid to myristic acid, myristic acid to palmitic acid, palmitic acid to stearic acid, palmitoleic acid to vaccenic acid, etc. It is known to control the elongation of carbon chains of fatty acids having 12 or more carbon atoms [J. Biol. Chem., 276 (48), 45358-45366, (2001) (Non-Patent Document 1). In addition, it is known that excessive long-chain fatty acids in a living body cause an increase in neutral fat, phospholipid, cholesteryl ester, and the like, thereby causing fat accumulation.

  Excessive accumulated fat causes, for example, insulin resistance, diabetes, hypertension, hyperlipidemia, obesity, etc., and these factors combine to increase the risk of developing arteriosclerosis. Such symptoms are called metabolic syndrome. Furthermore, high neutral fat or obesity is, for example, pancreatitis, liver dysfunction, cancer such as breast cancer / uterine cancer / ovarian cancer / colon cancer / prostate cancer, menstrual abnormality, arthritis, gout, cholecystitis, gastroesophageal reflux, obesity hypoventilation It is known to increase the risk of syndrome (Pickwick syndrome), sleep apnea syndrome and the like. In addition, it is well known that diabetes is likely to cause, for example, angina pectoris, heart failure, stroke, lameness, retinopathy, decreased visual acuity, renal failure, neuropathy, skin ulcer, infection, etc. [The Merck Manual of Medical Information (see The Merck Manual of Medical Information), second home edition, Merck & Co, 2003].

Therefore, LCE inhibitors are useful as preventive and / or therapeutic agents for these diseases.
As a conventionally known benzoxazinone derivative, for example, JP 2002-543193 A can be mentioned. This compound has a benzoxazinone skeleton, but the R ² portion in the present invention is limited to C 1-6 alkyl or C 2-6 alkenyl, which is different from the present invention. Furthermore, this reference relates to a progesterone receptor modulator, and there is no disclosure about the LCE inhibitory effect.
Furthermore, no compound having LCE inhibitory activity has been known at all.
Journal of Biological Chemistry (J. Biol. Chem.), 276 (48), 45358-45366, (2001) Special table 2002-543193

  An object of the present invention is to provide a compound having an LCE inhibitory action.

  As a result of intensive studies, the present inventors have found that the compound represented by the general formula (I) has an excellent LCE inhibitory action and completed the present invention.

That is, the present invention
(1) Formula (I)

［式中、
Ｒ^１は、ハロゲンで置換されていてもよいＣ_１−６アルキル又はハロゲンで置換されていてもよいＣ_３−８シクロアルキルを表し、
Ｒ^２は、

[Where:
R ¹ represents C _1-6 alkyl which may be substituted with halogen or C _3-8 cycloalkyl which may be substituted with halogen;
R ² is

よりなる群から選択される基を表し、ここで、
Ｗは、Ｃ_１−６アルキレン、Ｃ_２−６アルケニレン、Ｃ_２−６アルキニレン又はＣ_３−６シクロアルキレンを表し、前記アルキレン、アルケニレン、アルキニレン又はシクロアルキレンは、ハロゲンで置換されてもよいＣ_１−３アルキル、ハロゲンで置換されてもよいＣ_１−３アルキルオキシ、ヒドロキシル又はハロゲンで置換されていてもよく、
Ｒは、Ｃ_１−６アルキル、Ｃ_３−８シクロアルキル、アリール又はヘテロアリールを表し、ここで、前記Ｃ_１−６アルキル、Ｃ_３−８シクロアルキル、アリール又はヘテロアリールは、ハロゲン、ハロゲンで置換されていてもよいＣ_１−６アルキル、ハロゲンで置換されていてもよいＣ_１−６アルキルオキシ、Ｃ_１−６アルキルスルホニル、シアノ、フェニル、Ｃ_１−６アルキルチオ、ヒドロキシル、アミノ、Ｃ_１−６アルキルアミノ、ジＣ_１−６アルキルアミノ、ヒドロキシＣ_１−６アルキル、アミノＣ_１−６アルキル、Ｃ_１−６アルキルアミノＣ_１−６アルキル、ジＣ_１−６アルキルアミノアルキル、Ｃ_１−６アルコキシＣ_１−６アルキル、Ｃ_１−６アルキルカルボニル、Ｃ_１−６アルキルカルボニルアミノ、Ｃ_１−６アルキルカルバモイル、Ｃ_３−８シクロアルキルカルバモイル、Ｃ_１−６アルキルスルホニルアミノ又はＣ_１−６アルキルアミノスルホニルで置換されていてもよく、
Ｒ^３は、水素原子、Ｃ_１−６アルキル、アリール又はヘテロアリールを表し、
Ｘは、−Ｏ−、−Ｃ（Ｒ^４ａ）（Ｒ^４ｂ）−又は−ＮＲ^５−を表し、
Ｒ^４ａ、Ｒ^４ｂ及びＲ^５は、それぞれ独立して、水素、Ｃ_１−６アルキル、Ｃ_３−８シクロアルキル、アリール又はヘテロアリールを表し、ここで、前記Ｃ_１−６アルキル、Ｃ_３−８シクロアルキル、アリール又はヘテロアリールは、ハロゲン、ハロゲンで置換されていてもよいＣ_１−６アルキル、ハロゲンで置換されていてもよいＣ_１−６アルキルオキシ、Ｃ_１−６アルキルスルホニル、シアノ、アリール又はヘテロアリールで置換されていてもよく、
Ｙ_１は、−ＣＲ^６−又は−Ｎ−を表し、
Ｙ_２は、−ＣＲ^７−又は−Ｎ−を表し、
Ｙ_３は、−ＣＲ^８−又は−Ｎ−を表し、
Ｙ_４は、−ＣＲ^９−又は−Ｎ−を表し、
Ｒ^６、Ｒ^７、Ｒ^８及びＲ^９は、それぞれ独立して、水素原子、ハロゲン、シアノ、Ｃ_１−６アルキル、Ｃ_３−８シクロアルキル、Ｃ_１−６アルコキシ、ヒドロキシル、ヒドロキシＣ_１−６アルキル、アミノ、Ｃ_１−６アルキルアミノ、ジＣ_１−６アルキルアミノ、アミノＣ_１−６アルキル、Ｃ_１−６アルキルアミノＣ_１−６アルキル、ジＣ_１−６アルキルアミノ（Ｃ_１−６）アルキル、Ｃ_１−６アルコキシＣ_１−６アルキル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１−６アルキルスルホニル、Ｃ_１−６アルキルスルフィニル、Ｃ_１−６アルキルチオ、アリールスルホニル、ヘテロアリールスルホニル、アリールスルフィニル、ヘテロアリールスルフィニル、アリールチオ、ヘテロアリールチオ、Ｃ_１−６アルキルカルボニル、アリールカルボニル、ヘテロアリールカルボニル、Ｃ_１−６アルキルカルボニルアミノ、アリールカルボニルアミノ、ヘテロアリールカルボニルアミノ、Ｃ_１−６アルキルカルバモイル、Ｃ_３−８シクロアルキルカルバモイル、ヘテロシクリルカルバモイル、アリールカルバモイル、ヘテロアリールカルバモイル、Ｃ_１−６アルキルスルホニルアミノ、アリールスルホニルアミノ、ヘテロアリールスルホニルアミノ、Ｃ_１−６アルキルスルファモイル、アリールスルファモイル又はヘテロアリールスルファモイルを表し、ここで、前記アルキル、シクロアルキル、ヘテロシクリル、アリール又はヘテロアリールは、ハロゲン、ハロゲンで置換されていてもよいＣ_１−６アルキル、ハロゲンで置換されていてもよいＣ_１−６アルキルオキシ、Ｃ_１−６アルキルスルホニル、カルボキシル及びシアノよりなる群から選択される基で置換されていてもよい］で表される化合物又は薬学的に許容されるその塩、を提供する。

Represents a group selected from the group consisting of:
W _{is, C 1-6 alkylene, C 2-6} represents _alkenylene, a _{C 2-6} alkynylene or _{C 3-6} cycloalkylene, said alkylene, alkenylene, alkynylene or cycloalkylene, optionally _{C 1} be substituted with halogen _-3 alkyl, optionally substituted with halogen, C _1-3 alkyloxy, hydroxyl or halogen optionally substituted,
R represents C _1-6 alkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, aryl or heteroaryl is halogen or halogen. optionally substituted _{C 1-6} alkyl, is optionally _{C 1-6} alkyloxy substituted with _{halogen, C 1-6} alkylsulfonyl, cyano, _{phenyl, C 1-6} alkylthio, hydroxyl, amino, _{C 1 -6} alkylamino, diC _1-6 alkylamino, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, diC _1-6 alkylaminoalkyl, C _{1 -6} alkoxy _{C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6} A · The _{carbamoyl, C 3-8 cycloalkylcarbamoyl,} may be substituted with _{C 1-6} alkylsulfonylamino or _{C 1-6} alkylaminosulfonyl,
R ³ represents a hydrogen atom, C _1-6 alkyl, aryl or heteroaryl,
X represents —O—, —C (R ^4a ) (R ^4b ) —, or —NR ⁵ —;
R ^4a , R ^4b and R ⁵ each independently represents hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein the C _1-6 alkyl, C _{3− 8} cycloalkyl, aryl or heteroaryl, halogen, C _1-6 alkyl optionally substituted by halogen, halogen optionally substituted C _1-6 alkyloxy, C _1-6 alkylsulfonyl, cyano, Optionally substituted with aryl or heteroaryl,
Y ₁ represents —CR ⁶ — or —N—,
Y ₂ represents —CR ⁷ — or —N—,
Y ₃ represents —CR ⁸ — or —N—,
Y ₄ represents -CR ⁹ -or -N-,
R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, hydroxyl, hydroxy C _{1- 6} alkyl, amino, C _1-6 alkylamino, diC _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, diC _1-6 alkylamino (C _{1- 6) alkyl, C 1-6} alkoxy _{C 1-6} alkyl, heterocyclyl, aryl, _{heteroaryl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6} alkylthio, arylsulfonyl, heteroarylsulfonyl, aryl sulfinyl, heteroaryl arylsulfinyl, arylthio, _{heteroarylthio, C 1-6} alkyl Carbonyl, arylcarbonyl, _{heteroarylcarbonyl, C 1-6} alkylcarbonylamino, arylcarbonylamino, _{heteroarylcarbonylamino, C 1-6 alkylcarbamoyl, C 3-8} cycloalkylcarbamoyl, heterocyclylthio carbamoyl, arylcarbamoyl, hetero arylcarbamoyl C _1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, C _1-6 alkylsulfamoyl, arylsulfamoyl or heteroarylsulfamoyl, wherein said alkyl, cycloalkyl, heterocyclyl , aryl or heteroaryl, halogen, optionally substituted by halogen C _1-6 alkyl, a C _1-6 a optionally substituted by halogen Kiruokishi, C _1-6 alkylsulfonyl, a salt thereof, which is a compound or a pharmaceutically acceptable represented by carboxyl and optionally substituted by a group selected from the group consisting of cyano.

Furthermore, the present invention provides
(2) a long-chain fatty acid elongation enzyme (LCE) inhibitor comprising as an active ingredient the compound represented by formula (1) or a pharmaceutically acceptable salt thereof,
(3) A pharmaceutical composition comprising a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive,
(4) Metabolic syndrome, fatty liver, hyperlipidemia, dyslipidemia, nonalcoholic fatty liver, comprising the compound represented by formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, A therapeutic agent for obesity, diabetes, bulimia, malignant neoplasms or infectious diseases is provided.

  The meanings of terms used in the present specification are described below, and the present invention is described in more detail.

  Examples of “aryl” include phenyl, naphthyl and the like.

  "Heteroaryl" is a 5-membered or 6-membered monocyclic ring containing 1 or 2 or more, preferably 1 to 3 heteroatoms, which are the same or different from the group consisting of oxygen atom, nitrogen atom and sulfur atom. Or a fused cyclic heteroaryl in which the monocyclic heteroaryl is fused with the aryl, or the same or different monocyclic heteroaryl is fused with each other, such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl , Thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2 , 4-Triazinyl, 1 3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl , Pteridinyl, pyrido [3,2-b] pyridyl and the like.

  “Heterocyclyl” means monocyclic containing 4 to 10 atoms containing 1, 2 or 3 heteroatoms selected from saturated, partially saturated or unsaturated nitrogen, oxygen and sulfur, or Bicyclic rings such as pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidoneyl, pyridoneyl, dioxolanyl, tetrahydrofuranyl and tetrahydropyranyl are exemplified.

“C _3-8 cycloalkyl” means cycloalkyl having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

  “Halogen” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

“C _1-6 alkyl” means a linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert -Butyl, n-pentyl, isopentyl, n-hexyl, isohexyl and the like.

“C _1-6 alkylene” includes linear alkylene having 1 to 6 carbon atoms or branched alkylene having 3 to 6 carbon atoms, and specifically includes, for example, methylene, ethylene, propylene, butylene, pentylene. Hexylene and the like.

“C _2-6 alkenylene” includes linear or branched alkenylene having 2 to 6 carbon atoms containing one carbon-carbon double bond in the chain, specifically Examples include vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 1-hexenylene and the like.

“C _2-6 alkynylene” includes straight-chain alkynylene having 2 to 6 carbon atoms or branched alkynylene having 3 to 6 carbon atoms. Specific examples thereof include the following.

“C _3-6 cycloalkylene” includes cycloalkylene having 3 to 6 carbon atoms, specifically, for example, 1,1-cyclopropylene, 1,2-cyclopropylene, 1,1-cyclobutanylene, 1,2-cyclobutanylene, 1,3-cyclobutanylene, 1,1-cyclopentenylene, 1,2-cyclohexenylene, 1,3-cyclohexenylene, 1,4-cyclohexenylene and the like can be mentioned.

“C _1-6 alkyl optionally substituted with halogen” means 1 or 2 or more, preferably 1 to 3 C ₁ -C ₁ optionally substituted with the same or different halogen. ₆ alkyl, for example, in addition to unsubstituted C _1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, chloromethyl, 2-chloroethyl, 1,2-dichloro And halogen-substituted C _1-6 alkyl such as ethyl, bromomethyl, iodomethyl and the like. Similarly, C _1-3 alkyl optionally substituted with halogen is C 1 or 2 or more, preferably 1 to 3 C, optionally substituted with the same or different halogen. _It means _1-3 alkyl.

“C _1-6 alkoxy” is linear or branched alkoxy having 1 to 6 carbon atoms, and is also referred to as “C _1-6 alkyloxy”. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, Examples include tert-butoxy and pentyloxy.

“C _1-6 alkoxy optionally substituted with halogen” means 1 or 2 or more, preferably 1 to 3 carbon atoms which may be substituted with the same or different halogen, at any substitutable position. _-6 linear or branched alkoxy, such as chloromethoxy, fluoromethoxy, trifluoromethoxy, chloroethoxy, fluoroethoxy, dichloroethoxy, difluoroethoxy and the like in addition to unsubstituted C _1-6 alkoxy It is done. Similarly, “C _1-3 alkoxy optionally substituted with halogen” is one or more, preferably 1 to 3 carbon atoms optionally substituted with the same or different halogens described above. A linear or branched alkoxy having a number of 1 to 3 is meant.

“C _1-6 alkylsulfonyl” is a group in which C _1-6 alkyl is bonded to sulfonyl. Specifically, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl Etc.

“C _1-6 alkylsulfinyl” is a group in which C _1-6 alkyl is bonded to sulfinyl. Specifically, for example, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl Etc.

“C _1-6 alkylthio” is a group in which C _1-6 alkyl is bonded to a sulfur atom, and specific examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and the like. .

“C _1-6 alkylamino” is amino monosubstituted by the above C _1-6 alkyl, and examples thereof include methylamino, ethylamino, propylamino, isopropylamino, butylamino and the like.

“DiC _1-6 alkylamino” is amino disubstituted by the same or different C _1-6 alkyl, and examples thereof include dimethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino and the like. .

“C _1-6 alkylamino C _1-6 alkyl” means C _1-6 alkyl mono-substituted by the above C _1-6 alkylamino, which is methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylamino. And methyl.

“DiC _1-6 alkylamino C _1-6 alkyl” means C _1-6 alkyl monosubstituted by the di-C _1-6 alkylamino, such as dimethylaminomethyl, diethylaminomethyl, ethylmethylaminomethyl, etc. Is mentioned.

“Amino C _1-6 alkyl” is the above alkyl in which one of hydrogen atoms is substituted with an amino group, and examples thereof include aminomethyl, aminoethyl, aminopropyl, and the like.

“C _1-6 alkyloxy C _1-6 alkyl” means C _1-6 alkyl substituted with a C _1-6 alkyloxy group, specifically, for example, methoxymethyl, ethoxymethyl, n -Propyloxymethyl, isopropyloxymethyl, 1-methoxyethyl and the like.

“C _1-6 alkyloxycarbonyl” is a group in which C _1-6 alkyloxy is bonded to a carbonyl group (—CO—), and includes an alkyloxycarbonyl group having 1 to 6 carbon atoms, specifically Examples include methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl and the like.

“C _1-6 alkyloxycarbonylamino” is a group in which C _1-6 alkyloxycarbonyl is bonded to an amino group (—NH ₂ ), and includes alkyloxycarbonylamino having 1 to 6 carbon atoms. Specifically, for example, methoxycarbonylamino, ethoxycarbonylamino, n-propyloxycarbonylamino, isopropyloxycarbonylamino, n-butoxycarbonylamino and the like can be mentioned.

“C _1-6 alkyloxycarbonyl (C _1-6 alkyl) amino” is a group in which a lower alkyloxycarbonyl is bonded instead of a hydrogen atom on the nitrogen atom of mono-C _1-6 alkylamino, specifically Examples include methoxycarbonyl (methyl) amino, ethoxycarbonyl (methyl) amino, n-propyloxycarbonyl (methyl) amino, and the like.

“C _1-6 alkylcarbonyl” is a group in which C _1-6 alkyl is bonded to carbonyl, and includes alkylcarbonyl having 1 to 6 carbons, specifically, for example, acetyl, propionyl, butyryl, Examples include isobutyryl and valeryl.

“C _1-6 alkylcarbonyloxy” is a group in which C _1-6 alkylcarbonyl is bonded to an oxygen atom, and specifically includes, for example, acetoxy, propionyloxy, valeryloxy, isovaleryloxy, pivaloyloxy and the like. Can be mentioned.

“C _1-6 alkylcarbonylamino” is a group in which one hydrogen atom of an amino group is substituted with C _1-6 alkylcarbonyl. Specifically, for example, acetamide, propionylamino, isobutyrylamino, And valerylamino.

“C _1-6 alkylcarbonyl (C _1-6 alkyl) amino” is a group in which a hydrogen atom on a nitrogen atom of mono C _1-6 alkylamino is substituted with lower alkylcarbonyl, for example, methylcarbonyl (methyl ) Amino, ethylcarbonyl (methyl) amino, n-propylcarbonyl (methyl) amino and the like.

“Mono C _1-6 alkylcarbamoyl” is a group in which one of the hydrogen atoms of the carbamoyl group (—CONH ₂ ) is substituted with C _1-6 alkyl, and specifically includes, for example, methylcarbamoyl, ethylcarbamoyl, Examples include n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl and the like.

“Di-C _1-6 alkylcarbamoyl” is a group in which two hydrogen atoms of a carbamoyl group are substituted with C _1-6 alkyl. Specifically, for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, Examples include di (n-propyl) carbamoyl, methyl (n-propyl) carbamoyl, diisopropylcarbamoyl and the like. The di-C _1-6 alkylcarbamoyl includes those in which two alkyl groups together form a nitrogen-containing heterocyclyl together with a nitrogen atom.

“C _3-8 cycloalkylcarbamoyl” is a group in which one hydrogen atom of carbamoyl is substituted with C _3-8 cycloalkyl. Specific examples include cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl and the like. Is mentioned.

“Mono C _1-6 alkylcarbamoylamino” is a group in which one hydrogen atom of an amino group is substituted with mono C _1-6 alkylcarbamoyl. Specifically, for example, methylcarbamoylamino, ethylcarbamoylamino, Examples include n-propylcarbamoylamino, isopropylcarbamoylamino and the like.

The "di-C _1-6 alkylcarbamoyl amino" is 1 Tsugaji C _1-6 alkylcarbamoyl and substituted groups of the hydrogen atoms of an amino group, specifically, for example, dimethylcarbamoylamino, diethylcarbamoyl amino, Examples include di (n-propyl) carbamoylamino and diisopropylcarbamoylamino.

“Mono C _1-6 alkylcarbamoyl (C _1-6 alkyl) amino” is a group in which a hydrogen atom on the nitrogen atom of mono-lower alkylamino is substituted with mono-lower alkylcarbamoyl. Specifically, for example, And monomethylcarbamoyl (methyl) amino, monoethylcarbamoyl (methyl) amino, [mono (n-propyl) carbamoyl] (methyl) amino, and the like.

“DiC _1-6 alkylcarbamoyl (C _1-6 alkyl) amino” is a group in which a hydrogen atom on a nitrogen atom of mono C _1-6 alkylamino is substituted with a diC _1-6 alkylcarbamoyl group; Specific examples include dimethylcarbamoyl (methyl) amino, diethylcarbamoyl (methyl) amino, [di (n-propyl) carbamoyl] (methyl) amino, and the like.

“Mono C _1-6 alkylcarbamoyloxy” is a group in which mono C _1-6 alkylcarbamoyl is bonded to an oxygen atom, and specifically includes, for example, methylcarbamoyloxy, ethylcarbamoyloxy, n-propylcarbamoyloxy. And isopropylcarbamoyloxy.

“DiC _1-6 alkylcarbamoyloxy” is a group in which diC _1-6 alkylcarbamoyl is bonded to an oxygen atom. Specifically, for example, dimethylcarbamoyloxy, diethylcarbamoyloxy, ethylmethylcarbamoyloxy, Di (n-propyl) carbamoyloxy, methyl (n-propyl) carbamoyloxy and the like can be mentioned.

“C _1-6 alkylsulfonylamino” is a group in which one of the hydrogen atoms of the amino group is substituted with C _1-6 alkylsulfonyl. Specifically, for example, methylsulfonylamino, ethylsulfonylamino, n— And propylsulfonylamino, isopropylsulfonylamino and the like.

The “C _1-6 alkylsulfonyl (C _1-6 alkyl) amino group” is a group in which a hydrogen atom on a nitrogen atom of mono C _1-6 alkylamino is substituted with C _1-6 alkylsulfonyl. Examples include methanesulfonylmethylamino, ethanesulfonylmethylamino, n-propanesulfonylmethylamino and the like.

“Mono C _1-6 alkylsulfamoyl” is a group in which one hydrogen atom of a sulfamoyl group (—SO ₂ NH ₂ ) is substituted with C _1-6 alkyl. Famoyl, monoethylsulfamoyl, mono (n-propyl) sulfamoyl and the like can be mentioned.

“Di-C _1-6 alkylsulfamoyl” is a group in which two hydrogen atoms of a sulfamoyl group are each substituted with C _1-6 alkyl. Specifically, for example, dimethylsulfamoyl, diethylsulfamoyl Famoyl, di (n-propyl) sulfamoyl and the like can be mentioned.

“Mono C _1-6 alkylsulfamoylamino” is a group in which one hydrogen atom of an amino group is substituted with mono C _1-6 alkylsulfamoyl. Specifically, for example, (monomethylsulfamoylamino) Moyl) amino, (monoethylsulfamoyl) amino, [mono (n-propyl) sulfamoyl] amino and the like.

The "(di-C _1-6 alkylsulfamoyl) amino", a 1 Tsugaji C _1-6 alkylsulfamoyl and substituted groups of the hydrogen atoms of an amino group, specifically, for example, (dimethyl Sulfamoyl) amino, (diethylsulfamoyl) amino, (ethylmethylsulfamoyl) amino and the like.

The _{"mono-C 1-6} alkylsulfamoyl _{(C 1-6} alkyl) amino" refers to the group in which a hydrogen atom on the nitrogen atom of _{mono-C 1-6} alkylamino is substituted with a mono _{C 1-6} alkylsulfamoyl Specifically, for example, monomethylsulfamoyl (methyl) amino, monoethylsulfamoyl (methyl) amino, [mono (n-propyl) sulfamoyl] (methyl) amino and the like can be mentioned.

“DiC _1-6 alkylsulfamoyl (C _1-6 alkyl) amino” means a group in which a hydrogen atom on a nitrogen atom of mono C _1-6 alkylamino is substituted with diC _1-6 alkylsulfamoyl. Specifically, for example, dimethylsulfamoyl (methyl) amino, diethylsulfamoyl (methyl) amino, [di (n-propyl) sulfamoyl] (methyl) amino and the like can be mentioned.

  “Arylthio” is a group in which the aryl is bonded to a sulfur atom.

  “Heteroarylthio” is a group in which the heteroaryl is bonded to a sulfur atom.

  “Arylsulfonyl” is a group in which the aryl is bonded to sulfonyl.

  “Heteroarylsulfonyl” is a group in which the heteroaryl is bonded to sulfonyl.

  “Arylsulfonylamino” is a group in which one of the hydrogen atoms of an amino group is substituted with arylsulfonyl.

  “Heteroarylsulfonylamino” is a group in which one of the hydrogen atoms of an amino group is substituted with heteroarylsulfonyl.

  “Arylsulfinyl” is a group in which the aryl is bonded to sulfinyl.

  “Heteroarylsulfinyl” is a group in which the heteroaryl is bonded to sulfinyl.

  “Arylcarbonyl” is a group in which the aryl is bonded to carbonyl.

  “Heteroarylcarbonyl” is a group in which the heteroaryl is bonded to carbonyl.

  “Arylcarbonylamino” is a group in which one of the hydrogen atoms of the amino group is substituted with the arylcarbonyl.

  “Heteroarylcarbonylamino” is a group in which one of the hydrogen atoms of an amino group is substituted with the heteroarylcarbonyl.

  “Heterocyclylcarbamoyl” is a group in which one of the hydrogen atoms of carbamoyl is substituted with the heterocyclyl.

  “Arylcarbamoyl” is a group in which one of the hydrogen atoms of carbamoyl is substituted with the aryl.

  “Heteroarylcarbamoyl” is a group in which one of the hydrogen atoms of carbamoyl is substituted with the heteroaryl.

  “Arylsulfamoyl” is a group in which one of the hydrogen atoms of sulfamoyl is substituted with aryl.

  “Heteroarylsulfamoyl” is a group in which one of the hydrogen atoms of sulfamoyl is substituted with heteroaryl.

  The “salt” of the compound according to the present invention means a conventional pharmaceutically acceptable salt, and examples thereof include salts of acid addition salts in the basic functional group when having a basic functional group. .

  Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; for example, maleate, fumarate, tartrate, citrate, ascorbate, Organic acid salts such as trifluoroacetates; for example, sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, and the like.

  “Treatment agent” means a drug provided for the purpose of treatment and / or prevention against various diseases.

  In order to disclose the compound according to the present invention more specifically, the various symbols used in formula (I) and the like will be described in more detail by giving preferred specific examples.

R ¹ represents C _1-6 alkyl which may be substituted with halogen or C _3-8 cycloalkyl which may be substituted with halogen.

Specific examples of R ¹ include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2,2-chloroethyl, 2,2- C _1-6 alkyl such as difluoroethyl, trichloroethyl, trifluoroethyl, etc .; C _3-8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, etc. are exemplified and preferred Methyl, ethyl, trichloromethyl, trifluoromethyl and the like are recommended, and trifluoromethyl is particularly recommended.

R ² is

からなる群から選択される基を表し、ここで、
Ｗは、Ｃ_１−６アルキレン、Ｃ_２−６アルケニレン、Ｃ_２−６アルキニレン又はＣ_３−８シクロアルキレンを表し、該アルキレン、アルケニレン、アルキニレン又はシクロアルキレンは、ハロゲンで置換されてもよいＣ_１−３アルキル、ハロゲンで置換されてもよいＣ_１−３アルキルオキシ、ヒドロキシル又はハロゲンで置換されていてもよく、
Ｒは、Ｃ_１−６アルキル、Ｃ_３−８シクロアルキル、アリール又はヘテロアリールを表し、ここで、前記Ｃ_１−６アルキル、Ｃ_３−８シクロアルキル、アリール又はヘテロアリールは、ハロゲン、ハロゲンで置換されていてもよいＣ_１−６アルキル、ハロゲンで置換されていてもよいＣ_１−６アルキルオキシ、Ｃ_１−６アルキルスルホニル、シアノ、フェニル、Ｃ_１−６アルキルチオ、ヒドロキシル、アミノ、Ｃ_１−６アルキルアミノ、ジＣ_１−６アルキルアミノ、ヒドロキシＣ_１−６アルキル、アミノＣ_１−６アルキル、Ｃ_１−６アルキルアミノ（Ｃ_１−６）アルキル、ジＣ_１−６アルキルアミノ（Ｃ_１−６）アルキル、Ｃ_１−６アルコキシＣ_１−６アルキル、Ｃ_１−６アルキルカルボニル、Ｃ_１−６アルキルカルボニルアミノ、Ｃ_１−６アルキルカルバモイル、Ｃ_３−８シクロアルキルカルバモイル、Ｃ_１−６アルキルスルホニルアミノ又はＣ_１−６アルキルアミノスルホニルで置換されていてもよい。

Represents a group selected from the group consisting of:
W _{is, C 1-6 alkylene, C 2-6 alkenylene, C 2-6} represents alkynylene or _{C 3-8} cycloalkylene, said alkylene, alkenylene, alkynylene or cycloalkylene, optionally _{C 1} be substituted with halogen _-3 alkyl, optionally substituted with halogen, C _1-3 alkyloxy, hydroxyl or halogen optionally substituted,
R represents C _1-6 alkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, aryl or heteroaryl is halogen or halogen. optionally substituted _{C 1-6} alkyl, is optionally _{C 1-6} alkyloxy substituted with _{halogen, C 1-6} alkylsulfonyl, cyano, _{phenyl, C 1-6} alkylthio, hydroxyl, amino, _{C 1 -6} alkylamino, diC _1-6 alkylamino, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkylamino (C _1-6 ) alkyl, diC _1-6 alkylamino (C _1-6 ) alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkylcarbonyl Optionally substituted with Mino, C _1-6 alkylcarbamoyl, C _3-8 cycloalkylcarbamoyl, C _1-6 alkylsulfonylamino or C _1-6 alkylaminosulfonyl.

  Specifically as W,

等が例示され、好ましくは−ＣＨ_２−、−ＣＨ_２ＣＨ_２−、−ＣＨ_２ＣＨ_２ＣＨ_２−が推奨される。

Like are exemplified, preferably _{-CH 2 -, - CH 2 CH} 2 -, - CH 2 CH 2 CH 2 - it is recommended.

  Specific examples of R include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, fluorophenyl, chlorophenyl, difluorophenyl, methanesulfonylphenyl, Methylphenyl, isopropylphenyl, methoxyphenyl, trifluoromethylphenyl, cyanophenyl, naphthyl, pyridinyl, fluoropyridinyl, methylpyridinyl, trifluoromethylpyridinyl, methoxypyridinyl, pyrazinyl, pyridazinyl, imidazolyl, methylimidazolyl, benz Imidazolyl, oxazolyl, ethyloxazolyl, oxadiazolyl, thiazolyl, methylthiazolyl, thiadiazolyl, pyrrolidinyl, piperidy Le, morpholinyl and the like.

R in the formula (II-1) is preferably phenyl or heteroaryl (particularly pyridyl), and the phenyl or heteroaryl is halogen, cyano, C _1-6 alkyl _optionally substituted with halogen, halogen C _1-6 alkyloxy, C _1-6 alkylsulfonyl, C _1-6 alkylthio, hydroxyl, amino, C _1-6 alkylamino, di-C _1-6 alkylamino, hydroxy C _1- optionally substituted with ₆ alkyl, amino C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, diC _1-6 alkylamino C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _{1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbamoyl, C 3-8} cycloalkyl Carbamoyl, optionally substituted by C _1-6 alkylsulfonylamino and C _1-6 substituents selected from the group consisting of alkyl aminosulfonyl.

  More preferably, R in formula (II-1) is phenyl, fluorophenyl, chlorophenyl, tolyl, isopropylphenyl, methoxyphenyl, trifluoromethylphenyl, methanesulfonylphenyl; pyridyl, fluoropyridyl, methylpyridyl, trifluoromethylpyridyl, Methoxypyridyl and the like are recommended.

Further, W in the formula (II-1) is preferably —CH ₂ —, —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ —.

R and W in the formula (II-2) are preferably the same as those in the formula (II-1).
R and W in the formula (II-3) are preferably the same as those in the formula (II-1).
R and W in the formula (II-4) are preferably the same as those in the formula (II-1).
R and W in the formula (II-5) are preferably the same as those in the formula (II-1).
R and W in the formula (II-6) are preferably the same as those in the formula (II-1).

Among these, R ² is preferably represented by the formula (II-1), the formula (II-4) or the formula (II-6).

R ³ represents a hydrogen atom, C _1-6 alkyl, aryl or heteroaryl.

Specific examples of R ³ include a hydrogen atom, C _1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl; aryl such as phenyl and naphthyl; pyridinyl, pyrimidinyl, pyridazinyl , Pyrazyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, pyridazinyl, pyrazinyl, furyl, thienyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoxazolyl Zolyl, benzothiazolyl, benzoisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazoly Le, cinnolinyl, pteridinyl, pyrido [3,2-b] heteroaryl such as pyridyl and the like, and preferably a hydrogen atom recommended.

X represents —O—, —C (R ^4a ) (R ^4b ) — or —NR ⁵ —, and R ^4a , R ^4b and R ⁵ each independently represent hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl or heteroaryl is halogen, C _{1-6 optionally} substituted with halogen C _1-6 alkyloxy _optionally substituted with alkyl or halogen, C _1-6 alkylsulfonyl, cyano, aryl or heteroaryl may be substituted.

X is preferably —O— or —NR ⁵ —, and R ⁵ is, for example, a hydrogen atom, C _1-6 alkyl, C _3-6 cycloalkyl, etc. In particular, —O—, —NH -Etc. are recommended.

Y ₁ represents —CR ⁶ — or —N—,
Y ₂ represents —CR ⁷ — or —N—,
Y ₃ represents —CR ⁸ — or —N—,
Y ₄ represents —CR ⁹ — or —N—.

R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, hydroxyl, hydroxy C _{1- 6} alkyl, amino, C _1-6 alkylamino, diC _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, diC _1-6 alkylamino (C _{1- 6) alkyl, C 1-6} alkoxy _{C 1-6} alkyl, heterocyclyl, aryl, _{heteroaryl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6} alkylthio, arylsulfonyl, heteroarylsulfonyl, aryl sulfinyl, heteroaryl arylsulfinyl, arylthio, _{heteroarylthio, C 1-6} alkyl Carbonyl, arylcarbonyl, _{heteroarylcarbonyl, C 1-6} alkylcarbonylamino, arylcarbonylamino, _{heteroarylcarbonylamino, C 1-6 alkylcarbamoyl, C 3-8} cycloalkylcarbamoyl, heterocyclylthio carbamoyl, arylcarbamoyl, hetero arylcarbamoyl C _1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, C _1-6 alkylsulfamoyl, arylsulfamoyl or heteroarylsulfamoyl, wherein said alkyl, cycloalkyl, heterocyclyl , aryl or heteroaryl, halogen, optionally substituted by halogen C _1-6 alkyl, a C _1-6 a optionally substituted by halogen Kiruokishi, C _1-6 alkylsulfonyl, optionally substituted with a group selected from carboxyl and the group consisting of cyano.

Specifically, as Y ₁ , Y ₂ , Y ₃ and Y ₄ ,
^{-CR 6 -; - CR 7 -} ; - CR 8 -; - CR 9 -,
^{-N -; - CR 7 -;} - CR 8 -; - CR 9 -,
^{-CR 6 -; - N -;} - CR 8 -; - CR 9 -,
^{-CR 6 -; - CR 7 -} ; - N -; - CR 9 -,
^{-CR 6 -; - CR 7 -} ; - CR 8 -; - N-, and the like, more preferably ^{-CR 6 -; - CR 7 -} ; - CR 8 -; - CR 9 - , or -CR ⁶ - ^{; -CR 7 -; - N -} ; - CR 9 -
Is recommended.

As specific R ⁶ , R ⁷ , R ⁸ and R ⁹ , each independently,
Hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano, methyl, ethyl, methoxy, phenyl, carboxyphenyl, p-toluyl, pyridyl, methylpyridyl, methoxypyridyl, oxazole, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, N -Methylpyrazolyl, thienyl, furyl, methylcarbonylamino, ethylcarbonylamino, methylcarbamoyl, difluoroethylcarbamoyl, trifluoroethylcarbamoyl, cyclopentylcarbamoyl, tetrahydrofuranylcarbamoyl, pyrrolidone, pyridone and the like.

For Y ₁ , Y ₂ , Y ₃ and Y ₄ , when R ⁶ , R ⁷ , R ⁸ and R ⁹ are present, ie, —CR ⁶ —, —CR ⁷ —, —CR ⁸ — and —CR respectively ^{In the} case of ⁹ −, R ⁶ , R ⁷ , R ⁸ and R ⁹ are preferably
At least one of R ⁶ , R ⁷ , R ⁸ and R ⁹ is halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, hydroxyl, hydroxy C _1-6 alkyl Amino, C _1-6 alkylamino, diC _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, diC _1-6 alkylaminoalkyl, C _1-6 alkoxy _{C 1-6} alkyl, heterocyclyl, aryl, _{heteroaryl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6} alkylthio, arylsulfonyl, heteroarylsulfonyl, arylsulfinyl, heteroaryl arylsulfinyl, arylthio, Heteroarylthio, C _1-6 alkylcarbonyl, a Reelcarbonyl, heteroarylcarbonyl, C _1-6 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C _1-6 alkylcarbamoyl, C _3-8 cycloalkylcarbamoyl, heterocyclylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, C _1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, C _1-6 alkylsulfamoyl, arylsulfamoyl and heteroarylsulfamoyl, wherein said aryl or heteroaryl, halogen, optionally substituted by halogen _{C 1-6} alkyl, a _{C 1-6} alkyloxy optionally substituted with _{halogen, C 1-6} alkyl Sulfonyl, may be substituted with a group selected from the group consisting of carboxyl and cyano, and the remainder is recommended that a hydrogen atom.

As a preferable form as a compound represented by Formula (I), the compound represented by Formula (I-1) is illustrated. Here, R ¹ , R ² , R ³ , Y ₁ , Y ₂ , Y ₃ and Y ₄ are the same as described above.

Specifically, as the compound represented by the formula (I),
[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (pyridin-3-yl) carbamate,
[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (cyclopentyl) carbamate,
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide,
N-{[(4S ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide ,
N- {2- [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} -4-fluorobenzamide,
N- {2-[(4R ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} -4 -Fluorobenzamide,
N- {3- [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propyl} -4-fluorobenzamide,
N- {3-[(4R ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propyl} -4 -Fluorobenzamide,
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-methylbenzamide,
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -5-cyclopropylisoxazole-3 -Carboxamide,
3- [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N-pyridin-3-ylpropanamide,
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} pyridine-2-sulfonamide,
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzenesulfonamide,
N- {2- [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} benzenesulfonamide,
N- {3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propyl} pyridine-2-sulfonamide,
N- {3-[(4R ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propyl} pyridine- 2-sulfonamide,
N- {2- [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} pyridine-2-sulfonamide,
N- {2-[(4R ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} pyridine- 2-sulfonamide,
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -N '-(4-fluorophenyl) Urea,
N-{[(4S ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -N'- (4-fluorophenyl) urea,
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -N'-pyridin-4-ylurea ,
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide,
(4S ^* )-4-fluoro-N-{[2-oxo-6- (1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzo Oxazin-4-yl] methyl} benzamide,
4-Fluoro-N-{[6-isoxazol-4-yl-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl } Benzamide,
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-4-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide,
(4S ^* )-4-fluoro-N-{[2-oxo-6- (1H-pyrazol-4-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz Oxazin-4-yl] methyl} benzamide,
4-Fluoro-N-{[6- (1-methyl-1H-pyrazol-4-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide,
(4S ^* )-4-fluoro-N-{[6- (1-methyl-1H-pyrazol-4-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3 , 1-Benzoxazin-4-yl] methyl} benzamide,
4-Fluoro-N-{[6- (3-methyl-1H-pyrazol-5-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide,
4-Fluoro-N-{[6- (4-methyl-1H-pyrazol-5-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide,
4-Fluoro-N-{[2-oxo-6- (1H-pyrrol-2-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide,
4-Fluoro-N-{[6- (2-furyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide ,
4-Fluoro-N-{[2-oxo-6- (2-thienyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide ,
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzenesulfonamide,
4-Fluoro-N-{[(4S ^* )-2-oxo-6- (1H-pyrazol-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz Oxazin-4-yl] methyl} benzenesulfonamide,
N-{[2-oxo-6- (1H-pyrazol-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} pyridine -2-sulfonamide,
N-{[(4S ^* )-2-oxo-6- (1H-pyrazol-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-4- Yl] methyl} pyridine-2-sulfonamide,
4-Fluoro-N-({2-oxo-4- (trifluoromethyl) 6- [3- (trifluoromethyl) -1H-pyrazol-5-yl] -1,4-dihydro-2H-3,1 -Benzoxazin-4-yl} methyl) benzamide,
4-Fluoro-N-{[2-oxo-6- (2-oxopyrrolidin-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-4- Yl] methyl} benzamide,
(4S ^* )-4-fluoro-N-{[2-oxo-6- (2-oxopyrrolidin-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1- Benzoxazin-4-yl] methyl} benzamide,
4-fluoro-N-{[2-oxo-6- (propionylamino) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide,
4-fluoro-N-{[2-oxo-6- (1H-1,2,4-triazol-5-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1- Benzoxazin-4-yl] methyl} benzamide,
N-{[6- (benzoylamino) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide,
4-Fluoro-N-{[2-oxo-6- (2-oxo-1,3-oxazolidine-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1- Benzoxazin-4-yl] methyl} benzamide,
4-Fluoro-N-{[(4S ^* )-2-oxo-6- (2-oxo-1,3-oxazolidin-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H -3,1-benzoxazin-4-yl] methyl} benzamide,
4-Fluoro-N-{[6- (3-methyl-2-oxazolidine-1-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide,
4-Fluoro-N-{[2-oxo-6- (2-oxopyridin-1 (2H) -yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide,
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide,
4-Fluoro-N-{[(4S ^* )-2-oxo-6- (1H-pyrazol-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz Oxazin-4-yl] methyl} benzamide,
4-Fluoro-N-{[6- (4-methyl-1H-pyrazol-1-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide,
4-Fluoro-N-{[6- (3-methyl-1H-pyrazol-1-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide,
N-{[6- (3-Amino-1H-pyrazol-1-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl Methyl} -4-fluorobenzamide,
4-fluoro-N-{[2-oxo-4- (trifluoromethyl) -6- [3- (trifluoromethyl) -1H-pyrazol-1-yl] -1,4-dihydro-2H-3, 1-benzoxazin-4-yl] methyl} benzamide,
4-Fluoro-N-{[6-[(3S) -3-hydroxy-2-oxopyrrolidin-1-yl] -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3 , 1-Benzoxazin-4-yl] methyl} benzamide,
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} benzamide ,
4-Fluoro-N-{[(4S ^* ) 2-oxo-6- (1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl ] Methyl} benzamide,
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} 4-fluorobenzamide,
N-{[(4S ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} 4-fluorobenzamide,
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-4-yl) -4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} benzamide ,
N-{[2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide,
4-fluoro-N-{[2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide,
4-fluoro-N-{[6-methyl-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide,
N-{[2-oxo-6- (1H-pyrazol-4-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl } Pyridine-2-sulfonamide,
N-bicyclo [2.2.1] heptan-2-yl-4-{[(4-fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H -3,1-benzoxazine-6-carboxamide,
4-Fluoro-N-{[2-oxo-6- (3-phenyl-1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide and the like.

Production Method of Compound Represented by Formula (I) The compound represented by formula (I) can be prepared by the following method.
Manufacturing method 1
Production method 1 is a method for producing a compound represented by formula (I-Ia).

［式中、Ｗ’は、Ｗ又は保護されたＷを表し、特にＣ_１−６アルキレンが好ましく、他の記号は前記に同じである］

[Wherein W ′ represents W or protected W, particularly C _1-6 alkylene is preferable, and other symbols are the same as above]

Process 1
Compound 1 and Compound 2 are subjected to Grignard reaction in a reaction solvent to obtain Compound 3. As the usage-amount of the compound 2, 1-10 mol is illustrated with respect to 1 mol of compounds 1, Preferably 1-2 mol is recommended.

  Examples of the reaction solvent include diethyl ether, tetrahydrofuran (hereinafter referred to as “THF”), 1,4-dioxane (hereinafter referred to as “dioxane”), N, N-dimethylformamide (hereinafter referred to as “DMF”), and the like. The

  Examples of the reaction temperature include 0 to 100 ° C., and the reaction is usually completed in 1 to 24 hours. After the reaction, an acid is added to the reaction solution to stop the reaction to obtain compound 3.

  Compound 3 can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like (the same applies in the following reactions).

  Examples of compound 2 include methyl magnesium bromide. Examples of compound 1 include 2-amino-5-chloro-benzonitrile.

Process 2
Compound 3 is subjected to Grignard reaction with compound 4 to obtain a product, and then the obtained compound is reacted with carbonyldiimidazole (hereinafter referred to as “CDI”) to obtain compound 5.

  Examples of the compound 4 include vinyl magnesium bromide.

  The Grignard reaction can be carried out according to step 1.

  In the reaction between the obtained compound and CDI, the amount of CDI used is 1 to 5 mol, preferably 1 to 3 mol per mol of compound 3.

  Examples of the reaction solvent include methylene chloride, chloroform, diethyl ether, THF, dioxane and the like.

  Examples of the reaction temperature include 0 to 80 ° C., and the reaction is usually completed in 1 to 24 hours.

  For example, triphosgene can be used instead of CDI.

Process 3
Compound 6 is obtained by ozonolysis of compound 5 and reduction of the resulting product. The ozonolysis of compound 5 is carried out by aeration of ozone in compound 5, dichloromethane, chloroform, methanol, ethanol or the like or a mixed solvent thereof.

An example of the reaction temperature is -78 to 0 ° C, and the reaction is usually completed in 1 to 24 hours.
After removing ozone from the resulting reaction solution by nitrogen substitution or the like, sodium borohydride is added to the reaction system and reduced to obtain compound 6.

  Examples of the amount of sodium borohydride used include 1 to 10 mol, preferably 1 to 3 mol per mol of compound 5.

  Examples of the reaction temperature include 0 to 20 ° C., and the reaction is usually completed in 0.1 to 1 hour.

Process 4
A compound represented by the formula (I-1a) is obtained by condensing the compound 6 and the compound 7. Examples of the amount of compound 7 used include 1 to 3 mol, preferably 1 to 2 mol per mol of compound 6.

  Examples of the reaction solvent include methylene chloride, chloroform, diethyl ether, THF, dioxane, DMF and the like.

  Examples of the reaction temperature include 0 to 80 ° C., and the reaction is usually completed in 1 to 24 hours.

  Examples of compound 7 include 4-fluorophenyl isocyanate.

  The compound represented by the formula (I-1a) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It is the same in the reaction of

Manufacturing method 2
Production method 2 is a separate synthesis method of compound 3 using compound 8 as a raw material.
The production method 2 can also be performed according to a known method (J. Org. Chem. 1998, 63, 8536) or the like.

［式中、各記号は前記に同じである］

[Wherein each symbol is the same as above]

Process 5
Compound 9 is reacted with acid halide or acid anhydride in the reaction solvent in the presence of a base to give compound 9. Examples of the acid halide or acid anhydride include pivaloyl chloride, dicarbonate-di-t-butyl and the like. The amount of acid halide or acid anhydride used is 1 to 5 with respect to 1 mol of compound 8. Mole is exemplified, and preferably 1-2 mol is recommended.

  Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide and the like. The amount of the base used is 1 to 3 mol per 1 mol of compound 8. Exemplified, preferably 1-2 mol is recommended.

  Examples of the reaction solvent include THF, dioxane, t-butyl methyl ether, or a mixed solvent thereof.

  Examples of the reaction temperature include 0 to 50 ° C., and the reaction is usually completed in 1 to 24 hours.

  Examples of compound 8 include 4-chloroaniline and the like.

Step 6
After the compound 9 is treated with a base in a reaction solvent, the resulting product is subsequently reacted with the compound 10 to obtain a compound 11 through deprotection.

  That is, n-butyllithium and tetramethylethylenediamine (hereinafter referred to as “TMEDA”) are added to a THF solution of Compound 9, and the reaction is performed at −20 to 0 ° C. for about 30 minutes. Subsequently, compound 10 is added and the reaction is carried out at −78 to 0 ° C. for 1 to 10 hours. An acid is added to the obtained product, and deprotection is performed by stirring at 0 to 50 ° C. for 0.1 to 2 hours to obtain Compound 11.

  Compound 10 is exemplified by ethyl trifluoroacetate and the like.

  Examples of the acid include sulfuric acid, nitric acid, acetic acid, or a mixture thereof. Examples of the amount used include 5 to 100 mol per 1 mol of compound 9.

Step 7
Compound 3 is obtained by treating compound 11 with a base in a reaction solvent.

  Examples of the base include sodium hydroxide, sodium acetate, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide and the like, and the amount of the base used is 1 to 10 mol with respect to 1 mol of the compound 11. Preferably 1-3 moles are recommended.

  Examples of the reaction solvent include ether solvents such as THF, dioxane, t-butyl methyl ether, water, or a mixed solvent thereof.

  Examples of the reaction temperature include 0 to 50 ° C., preferably 0 to 30 ° C., and the reaction is usually completed in 0.1 to 1 hour.

  The compound 3 thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

Manufacturing method 3
Production method 3 is a method for producing a compound represented by formula (I-1b).

［式中、各記号は前記に同じである］

[Wherein each symbol is the same as above]

Process 8
In a reaction solvent, Compound 6 and trifluoromethanesulfonic anhydride are reacted in the presence of a base, and then the resulting compound is reacted with sodium azide to obtain Compound 12.

  The amount of trifluoromethanesulfonic anhydride used is 1 to 5 mol, preferably 1 to 3 mol per mol of compound 6.

  Examples of the base include triethylamine, diisopropylethylamine, 2,6-lutidine, pyridine and the like. The amount of the base used is 1 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of compound 6. The

  Examples of the reaction solvent include methylene chloride, chloroform, diethyl ether, THF, DMF and the like.

  Examples of the reaction temperature include 0 to 60 ° C., preferably 0 to 30 ° C., and the reaction is usually completed in 1 to 3 hours.

  The obtained intermediate can be used in the next reaction as it is, but the next reaction may be performed after isolation and purification.

  That is, compound 12 is obtained by reacting the obtained intermediate with sodium azide in a reaction solvent. Examples of the amount of sodium azide used include 1 to 10 mol, preferably 1 to 5 mol per mol of compound 6.

  Examples of the reaction solvent include methylene chloride, chloroform, diethyl ether, THF, DMF and the like.

  Examples of the reaction temperature include 0 to 100 ° C., preferably 0 to 80 ° C., and the reaction is usually completed in 6 to 24 hours.

Step 9
Compound 12 is reacted with trimethyl phosphite in a reaction solvent to obtain Compound 13.

  The amount of trimethyl phosphite to be used is exemplified by 1 to 3 mol, preferably 1 to 1.5 mol based on 1 mol of Compound 12.

  Examples of the reaction solvent include THF, dioxane, THF-water mixed solvent and the like.

  Examples of the reaction temperature include 0 to 100 ° C., preferably 0 to 80 ° C., and the reaction is usually completed in 1 to 24 hours.

Step 10
Compound 14 is obtained by treating compound 13 with an acid. Examples of the acid include 4N hydrochloric acid / dioxane.

  Examples of the amount of the acid used include 10 to 100 mol per mol of compound 13.

  Examples of the reaction temperature include 0 to 100 ° C., preferably 25 to 80 ° C., and the reaction is usually completed in 6 to 24 hours.

Step 11
A compound represented by the formula (I-1b) is obtained by condensing the compound 14 and the compound 15.

  Condensation can be carried out by a conventionally known method, in which compound 14 and compound 15 are reacted in the presence of a condensing agent, or the carboxylic acid moiety of compound 15 is activated by a conventionally known method to reactivate. Examples of the method include making a derivative and then amidating the derivative and compound 14 (see “Basics and Experiments of Peptide Synthesis” (Nobuo Izumiya et al., Maruzen Co., 1983)).

  For example, the following method is exemplified as the reaction using a condensing agent.

  That is, the compound 15 and the compound 14 are condensed in a reaction solvent using a condensing agent to obtain a compound represented by the formula (I-1b).

  As the usage-amount of the compound 15, 1-3 mol is illustrated with respect to 1 mol of compounds 14.

  Examples of the condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, and the amount of the condensing agent used is 1 to 3 mol per mol of compound 14. The

  Further, for the purpose of promoting the reaction, hydroxybenzotriazole (hereinafter referred to as “HOBT”) or the like may be added to the reaction system. The amount of HOBT used is exemplified by 1 to 3 moles per mole of Compound 14.

  Examples of the reaction solvent include THF, dioxane, DMF, DMSO, dichloromethane, or a mixed solvent thereof.

  The reaction temperature is, for example, 20 to 100 ° C., preferably 20 to 50 ° C. is recommended, and the reaction is usually completed in 1 to 24 hours.

  Examples of the compound 15 include 4-fluorobenzoic acid.

  The compound represented by the formula (I-1b) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

Manufacturing method 4
Production method 4 is a method for producing a compound represented by formula (I-1c).

［式中、Ｗ'’は、Ｗ’と同義であり、特にＣ_１−５アルキレンが好ましく、他の記号は前記に同じである］

[Wherein W ″ is synonymous with W ′, and in particular, C _1-5 alkylene is preferable, and other symbols are the same as above]

Step 12
Compound 16 is obtained by oxidizing compound 6 in a reaction solvent. Although the oxidation method is not particularly limited, for example, it can be performed using chromic acid / concentrated sulfuric acid.

  The amount of chromic acid used is 1 to 3 moles per mole of Compound 6, and the amount of concentrated sulfuric acid used is 1 to 20 moles per mole of Compound 6.

  An example of the reaction solvent is a mixed solvent of acetone and water.

  Examples of the reaction temperature include 0 to 50 ° C., preferably 0 to 30 ° C., and the reaction is usually completed in 1 to 24 hours.

Step 13
A compound represented by the formula (I-1c) is obtained by condensing the compound 16 and the compound 17. Although the method of condensation is not particularly limited, for example, it can be carried out according to Step 11.

  The compound represented by the formula (I-1c) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

Manufacturing method 5
Production method 5 is a method for producing a compound represented by formula (I-1d) or formula (I-1e).

［式中、各記号は前記に同じである］

[Wherein each symbol is the same as above]

Step 14
The compound represented by formula (I-1d) is obtained by reacting compound 14 and compound 18 in a reaction solvent in the presence of a base.

  The amount of compound 18 used is 1 to 5 moles per mole of compound 14, and preferably 1 to 3 moles.

  Examples of the base include triethylamine, diisopropylethylamine, 2,6-lutidine, pyridine and the like. The amount of the base used is 1 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of the compound 14. The

  Examples of the reaction solvent include THF, dioxane, DMF, DMSO, dichloromethane, or a mixed solvent thereof.

  Examples of the reaction temperature include 0 to 60 ° C., preferably 0 to 30 ° C., and the reaction is usually completed in 1 to 24 hours.

Step 15
The compound represented by formula (I-1e) is obtained by reacting compound 14 and compound 7 in the presence of a base in a reaction solvent.

  As the usage-amount of the compound 7, 1-5 mol is illustrated with respect to 1 mol of compounds 14, Preferably 1-3 mol is recommended.

  Examples of the base include triethylamine, diisopropylethylamine, 2,6-lutidine, pyridine and the like. The amount of the base used is 1 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of the compound 14. The

  Examples of the reaction solvent include THF, dioxane, DMF, DMSO, dichloromethane, or a mixed solvent thereof.

  Examples of the reaction temperature include 0 to 50 ° C., preferably 0 to 30 ° C., and the reaction is usually completed in 1 to 24 hours.

  Examples of the compound 18 include benzenesulfonyl chloride.

  The compound represented by the formula (I-1d) or (I-1e) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. Can be purified.

Manufacturing method 6
Production method 6 is a method for producing a compound having a substituent of R ^{6 to} R ⁹ in formula (I).

［式中、Ｒ^６−９は、Ｒ^６乃至Ｒ^９のいずれかを意味し、他の記号は前記に同じである］

[Wherein R ^6-9 means any one of R ^{6 to} R ⁹ , and other symbols are the same as above]

Step 16
Compound 19 is reacted with Compound 10 in the presence of a base in a reaction solvent to give Compound 20. The usage-amount of the compound 10 is 1-5 mol with respect to 1 mol of compound 19, Preferably 1-3 mol is recommended.

  Examples of the base include lithium diisopropylamide, and the amount used thereof is 1 to 5 mol, preferably 1 to 2 mol, based on 1 mol of compound 19.

  Examples of the reaction solvent include THF, diethyl ether, DMF and the like.

  As the reaction temperature, -78 to 100 ° C is exemplified, preferably -78 to 0 ° C is recommended, and the reaction is usually completed in 1 to 24 hours.

Step 17
Compound 20 is reacted with 4-methoxybenzylamine in the presence of a base in a reaction solvent to give compound 21.

  Examples of the amount of 4-methoxybenzylamine used include 1 to 10 mol, preferably 1 to 5 mol per mol of compound 20.

  Examples of the base include potassium carbonate, triethylamine and the like, and the amount used thereof is 1 to 10 moles, preferably 1 to 5 moles per mole of the compound 20.

  Examples of the reaction solvent include toluene, xylene and the like.

  Examples of the reaction temperature include 0 to 100 ° C., preferably 50 to 100 ° C., and the reaction is usually completed in 1 to 24 hours.

Step 18
Compound 21 is reacted according to step 2 to give compound 22. The reaction conditions are the same as in step 2.

Step 19
Compound 23 is obtained by using compound 22 according to production method 1 or combining them.

Step 20
Compound 24 is reacted with ceric ammonium nitrate (CAN) in a reaction solvent to give compound 24.

  As the usage-amount of CAN, 1-10 mol is illustrated with respect to 1 mol of compounds 23, Preferably 1-5 mol is recommended.

  Examples of the reaction solvent include a mixed solvent of acetonitrile and water.

  As the reaction temperature, 0 to 100 ° C. is exemplified, preferably 0 to 50 ° C. is recommended, and the reaction is usually completed in 1 to 24 hours.

Step 21
The compound 24 is reacted with the compound 25 in the presence of a palladium chloride.1,1-bis (diphenylphosphino) ferrocene complex and a base to obtain a compound represented by the formula (I-2a).

  The amount of compound 25 used is, for example, 1 to 5 mol, preferably 2 to 4 mol per mol of compound 24.

  The amount of the palladium chloride / 1,1-bis (diphenylphosphino) ferrocene complex used is 0.1 to 1.0 mol, preferably 0.1 to 0.3 mol, per 1 mol of compound 24. Is recommended.

  Examples of the base include potassium phosphate, potassium carbonate, sodium hydrogen carbonate and the like, and the amount used in this case is 1 to 5 mol per 1 mol of compound 24.

  The reaction is preferably performed under microwave irradiation.

  An example of the reaction solvent is a mixed solvent of DMF-water.

  The reaction temperature is, for example, 20 to 150 ° C., preferably 80 to 120 ° C., and the reaction is usually completed in 1 to 24 hours.

  Examples of the compound 25 include 3-pyrazole boronic acid.

  The compound represented by the formula (I-2a) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

Manufacturing method 7
Production method 7 is a separate production method for compounds having various substituents as R ^{6 to} R ⁹ in formula (I).

［式中、Ｒ^４１、Ｒ^４２、Ｒ^４３及びＲ^４４は、それぞれ独立して、水素原子、Ｃ_１−６アルキル、Ｃ_３−８シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール等を表し、他の記号は前記に同じである］

[Wherein, R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ each independently represents a hydrogen atom, C _1-6 alkyl, C _3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, etc. The symbols are the same as above]

Step 22
Compound 26 is reacted with Compound 27 in the presence of cesium carbonate, xanthophos and tris (dibenzylideneacetone) dipalladium to give Compound 28.

  The amount of compound 27 used is, for example, 1 to 10 mol, preferably 1 to 5 mol per mol of compound 26.

  Examples of the amount of xanthophos and tris (dibenzylideneacetone) dipalladium used are 0.01 to 1 mol and 0.01 to 1 mol, respectively, with respect to 1 mol of compound 26.

  Moreover, as a usage-amount of a cesium carbonate, 1-10 mol is illustrated with respect to 1 mol of compounds 26, Preferably 1-3 mol is recommended.

  Examples of the reaction solvent include DMF, THF, dioxane and the like. The reaction temperature is, for example, 30 to 150 ° C., preferably 60 to 120 ° C., and the reaction is usually completed in 1 to 24 hours.

  Examples of compound 27 include 2-pyrrolidinone.

Step 23
The compound represented by formula (I-2b) is obtained by deprotecting the p-methoxybenzyl group of compound 28. Deprotection is carried out by treating compound 28 with aluminum chloride in the presence of anisole in a reaction solvent.

  Examples of the amount of aluminum chloride used include 1 to 20 mol, preferably 5 to 15 mol per mol of compound 28.

  Moreover, as an usage-amount of anisole, 5-50 mol is illustrated with respect to 1 mol of compounds 28, Preferably 10-20 mol is recommended.

  In this reaction, anisole can be used as a reaction solvent, but a solvent such as dichloroethane may be used.

  The reaction temperature is, for example, 20 to 150 ° C., preferably 60 to 120 ° C., and the reaction is usually completed in 1 to 24 hours.

Step 24
Compound 26 is reacted with Compound 29 in the presence of tetrakis (triphenylphosphine) palladium in a reaction solvent to obtain Compound 30.

  The amount of tetrakis (triphenylphosphine) palladium used is, for example, 0.01 to 1 mol, preferably 0.01 to 0.2 mol based on 1 mol of compound 26.

  Moreover, as the usage-amount of the compound 29, 1-10 mol is illustrated with respect to 1 mol of compounds 26, Preferably 1-5 mol is recommended.

  Examples of the reaction solvent include DMF, THF, dioxane and the like.

  The reaction temperature is, for example, 20 to 150 ° C., preferably 50 to 100 ° C., and the reaction is usually completed in 1 to 24 hours.

  Examples of compound 29 include (1H-imidazol-2-yl) zinc bromide.

Step 25
The compound represented by formula (I-2c) is obtained by deprotecting the p-methoxybenzyl group of Compound 30 by the method described in Protective Groups in Organic Synthesis described below.

Step 26
Compound 26 is reacted with zinc cyanide in the presence of tetrakis (triphenylphosphine) palladium in a reaction solvent such as DMF to obtain compound 31. Reaction conditions are in accordance with step 17.

Step 27
The cyano group of compound 31 is hydrolyzed with hydrogen bromide to obtain compound 32.

  Examples of the amount of hydrogen bromide used include 1 to 20 mol per mol of compound 31. The reaction temperature is, for example, 50 to 150 ° C., preferably 50 to 100 ° C., and the reaction is usually completed in 1 to 24 hours.

Step 28
Compound 32 and Compound 33 are amidated according to Step 13 to obtain a compound represented by the formula (I-2d). The amidation method can be performed according to Step 11.

  Examples of the compound 33 include 4-fluoroaniline and the like.

  The compounds represented by formula (I-2b), formula (I-2c) and formula (I-2d) thus obtained can be obtained by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation. It can be isolated and purified by chromatography or the like.

Manufacturing method 8
Production method 8 is a separate production method for compounds having various nitrogen-containing substituents as R ^{6 to} R ⁹ in formula (I).

［式中、各記号は前記に同じである］

[Wherein each symbol is the same as above]

Step 29
Compound 26 is reacted in a reaction solvent using sodium iodide and copper iodide in the presence of a ligand to obtain compound 34.

  As usage-amount of sodium iodide and copper iodide, 1-20 mol of sodium iodide with respect to 1 mol of compounds 26, Preferably 1-5 mol is illustrated, and copper iodide is 0.1-0.1 mol. 2 mol, preferably 0.2 to 1 mol is exemplified.

  As the ligand, N, N-dimethylethylenediamine and the like are exemplified, and the use amount thereof is 0.1 to 3 mol, preferably 0.2 to 2 mol, relative to 1 mol of compound 26. The

  Examples of the reaction solvent include diethyl ether, THF, dioxane and the like.

  The reaction temperature is, for example, 20 to 150 ° C., preferably 50 to 120 ° C., and the reaction is usually completed in 1 to 48 hours.

Step 30
In a reaction solvent, Compound 34 is reacted with a nitrogen-containing compound (Compound 35) in the presence of a ligand, copper iodide and potassium phosphate to obtain Compound 36.

  As usage-amount of copper iodide and potassium phosphate, with respect to 1 mol of compounds 34, copper iodide is 0.1-2 mol, Preferably 0.1-1 mol is illustrated, and potassium phosphate is 1-10 mol, Preferably 1-3 mol is illustrated.

  Examples of the compound 35 include imidazole, triazole, tetrazole, pyrrolidone, and the like, and the amount used is 1 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of the compound 34.

As the ligand, N, N-dimethylethylenediamine and the like are exemplified, and the use amount thereof is 0.1 to 3 mol, preferably 0.2 to 2 mol, relative to 1 mol of compound 26. The
Examples of the reaction solvent include diethyl ether, THF, dioxane and the like.

  The reaction temperature is, for example, 20 to 150 ° C., preferably 50 to 120 ° C., and the reaction is usually completed in 1 to 24 hours.

Step 31
The protecting group of compound 36 is deprotected according to step 23 to obtain the compound represented by formula (I-2e).

  The compound represented by the formula (I-2e) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

Manufacturing method 9
Production method 9 is a method for producing a compound in which X is —NR ⁵ — in formula (I).

［式中、Ｐは、４-メトキシベンジル基等の保護基を表すか又は水素を表し、他の記号は前記に同じである］

[Wherein P represents a protecting group such as a 4-methoxybenzyl group or represents hydrogen, and other symbols are the same as above]

Step 32
Compound 3 ′ is reacted with KOCN in a reaction solvent to obtain compound 37. As the usage-amount of KOCN, 1-10 mol is illustrated with respect to 1 mol of compounds 3 ', Preferably 1-5 mol is recommended. Compound 3 ′ is the same as compound 3 or has an amino group protected.

  Examples of the reaction temperature include 30 to 100 ° C., preferably 50 to 80 ° C., and the reaction is usually completed in 1 to 24 hours.

  Examples of the reaction solvent include a mixed solvent of acetic acid and water.

Step 33
Compound 37 is reacted in the presence of p-toluenesulfonic acid in a reaction solvent to obtain compound 38.

  Examples of the amount of p-toluenesulfonic acid used include 0.01 to 1 mol, preferably 0.01 to 0.1 mol, relative to 1 mol of compound 37.

  Examples of the reaction solvent include benzene, toluene, xylene and the like.

  Examples of the reaction temperature include 50 ° C. to the boiling point of the solvent, and the reaction is usually completed in 1 to 12 hours.

Step 34
Compound 38 is reacted with nitromethane in the presence of a base to give compound 39.

  The amount of nitromethane to be used is exemplified by 1 to 100 mol, preferably 1 to 20 mol, per 1 mol of compound 38. Nitromethane may be used as a solvent.

  Examples of the base include diisopropylethylamine, triethylamine and the like, and the amount used thereof is 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of the compound 38.

  Examples of the reaction solvent include benzene, toluene, xylene and the like.

  An example of the reaction temperature is 30 to 100 ° C. The reaction is usually completed in 1 to 12 hours.

Step 35
Reduction of the nitro group of compound 39 with iron / ammonium chloride provides compound 40.

  The amount of iron / ammonium chloride used is, for example, 1 to 10 moles of iron with respect to 1 mole of compound 39, preferably 1 to 5 moles is recommended, while the amount of ammonium chloride used is 1 -10 mol is illustrated, preferably 1-5 mol is recommended.

  An example of the reaction temperature is 30 to 120 ° C. The reaction is usually completed in 1 to 24 hours.

  An example of the reaction solvent is a methanol-water mixed solvent.

Step 36
Compound 40 is condensed with Compound 15 according to Step 11 to give Compound 41.

Step 37
Compound 41 is reacted with compound 42 in the presence of a base to give compound 43. The amount of the base used is, for example, 1 to 20 mol, preferably 1 to 5 mol based on 1 mol of compound 41.

  As the base, potassium carbonate, sodium hydride and the like are used.

  The amount of compound 42 used is, for example, 1 to 20 mol, preferably 1 to 5 mol based on 1 mol of compound 41.

  As the compound 42, methyl iodide, ethyl iodide, benzyl bromide or the like is used.

Step 38
Using compound 43, deprotection is carried out by a method according to step 20 to obtain the compound represented by formula (I-2f). Deprotection may be performed according to the method described in Protective Groups in Organic Synthesis.

Step 39
Compound 40 and compound 18 are reacted according to step 14 to obtain the compound represented by formula (I-2g).

  The compound represented by the formula (I-2f) or the compound represented by the formula (I-2g) thus obtained can be obtained by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography. It can be isolated and purified by chromatography or the like.

  In the above production method, when an amino group, imino group, hydroxyl group, carboxyl group, oxo group, carbonyl group, etc. that do not participate in the reaction are present in the reactant, the amino group, hydroxyl group, carboxyl group, oxo group, carbonyl group is As appropriate, after protecting with an amino-protecting group, a hydroxyl-protecting group, a carboxyl-protecting group, an oxo group or a carbonyl-protecting group, each reaction of the above production method is performed, and the protecting group is removed after the reaction. Can do.

  The introduction and removal of the protecting group varies depending on the kind of the protecting group and the stability of the target compound. For example, the method described in the literature [Protective Groups in Organic Synthesis, T., et al. W. Greene, John Wiley & Sons (1981)] or a method analogous thereto, eg, solvolysis using an acid or base, ie, for example, 0.01 mole to large excess of acid, preferably trifluoroacetic acid, formic acid, Hydrochloric acid or the like, or an equimolar or large excess base, preferably potassium hydroxide, calcium hydroxide or the like; chemical reduction using a metal hydride complex or the like; catalytic reduction using a palladium-carbon catalyst, Raney nickel catalyst or the like Etc.

The protecting group for the amino group is not particularly limited as long as it has the function. For example, an aralkyl group such as a benzyl group, a p-methoxybenzyl group or a 3,4-dimethoxybenzyl group; an acetyl group, C _1-6 alkanoyl group such as pivaloyl group; benzoyl group; aryl alkanoyl group such as phenylacetyl group; C _1-6 alkoxycarbonyl group such as ethoxycarbonyl group t-butoxycarbonyl group; alkyloxycarbonyl such as benzyloxycarbonyl group Groups: C _1-6 alkylsilyl groups such as trimethylsilyl group and t-butyldimethylsilyl group; tetrahydropyranyl group; trimethylsilylethoxymethyl group; arylsulfonyl groups such as toluenesulfonyl group; Group, t-butoxycarbonyl , Trimethylsilyl ethoxymethyl group, such as methyl sulfonyl group is preferred.

The hydroxyl-protecting group is not particularly limited as long as it has the function. For example, a C _1-6 alkyl group such as a methyl group, an ethyl group, or a propyl group; a trimethylsilyl group, t-butyldimethylsilyl C _1-6 alkylsilyl group such as a group; C _1-6 alkoxymethyl group such as methoxymethyl group and 2-methoxyethoxymethyl group; tetrahydropyranyl group; trimethylsilylethoxymethyl group; benzyl group, p-methoxybenzyl group and the like And an acetyl group such as an acetyl group, and a methyl group, a methoxymethyl group, a tetrahydropyranyl group, a trimethylsilylethoxymethyl group, a t-butyldimethylsilyl group, an acetyl group, and the like are particularly preferable.

The protecting group for the carboxyl group is not particularly limited as long as it has the function, and examples thereof include C _1-6 alkyl groups such as a methyl group and an ethyl group; 2,2,2-trichloroethyl groups and the like. Halo C _1-6 alkyl group; aralkyl groups such as benzyl group and p-methoxybenzyl group, and the like, in particular, methyl group, ethyl group, t-butyl group, 2-propenyl group, benzyl group, p-methoxy A benzyl group and the like are preferable.

  The protecting group for the oxo group and carbonyl group is not particularly limited as long as it has the function thereof, and examples thereof include acetals such as ethylene ketals, dimethyl ketals, and S, S′-dimethyl ketals, and ketals. It is done.

  The compound of the present invention thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

  These compounds can be converted into pharmaceutically acceptable salts according to conventional methods, and conversely, conversion of salts into free compounds can also be performed according to conventional methods.

  The compound of the present invention may have stereoisomers or tautomers such as optical isomers, diastereoisomers and geometric isomers depending on the mode of the substituents. And stereoisomers, tautomers and mixtures thereof.

The usefulness of the compound according to the present invention as a medicine is proved, for example, in the following pharmacological test examples.
Pharmacological test example 1 (LCE enzyme activity inhibition test)
The test compound was dissolved in dimethyl sulfoxide (DMSO) to a concentration of 10 mM and further diluted with DMSO to prepare a 1000-fold concentrated solution of the evaluation concentration. The LCE enzyme activity inhibition test was performed by improving the method of Moon (J. Biol. Chem., 276, 45358-45366 (2001)). That is, after adding diluted test compound to a 96-well assay plate (Corning, 96-well assay block) 1.0 μL per well, 50 μL phosphate buffer solution (100 mM potassium phosphate buffer solution (pH 6.5)) , 25 μL of substrate solution (100 mM potassium phosphate buffer (pH 6.5), 4.0 μM rotenone, 80 μM fatty acid-free bovine serum albumin, 160 μM palmitoyl CoA, 80 μM malonyl CoA, 3.5 μM [ ¹⁴ C] -malonyl CoA ( 1.92 GBq / mmol, manufactured by Amersham)) is added to each well, and 25 μL of enzyme solution (100 mM potassium phosphate buffer (pH 6.5), 100 μg / mL human LCE) is added and the top of the plate is sealed with a seal And mild at 37 ° C for 90 minutes It was incubated with stirring crab shaking. Thereafter, 100 μL of 5N HCl was added to each well and the assay plate was agitated at room temperature for 5 minutes to stop the enzyme reaction and hydrolyze acyl CoA. Thereafter, the enzyme reaction solution in each well was adsorbed to each well of a 96-well GF / C filter plate (PerkinElmer Unifilter 96GF / C) in which water was passed in advance, and each well was washed with water to remove the non-adsorbed solution. After removing the malonyl CoA, the GF / C filter plate was dried at 50 ° C. for 60 minutes. Thereafter, 30 μL of scintillator (PerkinElmer micro scintillation 0) was added to each well to seal the upper part of the plate, and the immobilized [ ¹⁴ C] radioactivity was measured with a microplate scintillation counter (PerkinElmer top count) as enzyme activity. . The enzyme inhibitory activity of human LCE by the test compound was calculated using the radioactivity in a well containing DMSO not containing the test compound as a control. When the activity of the compounds of the present invention was examined using this assay, these compounds inhibited the activity of human LCE. The results are shown in Table 1.

  The compound represented by the general formula (I) can be administered orally or parenterally, and formulated into a form suitable for such administration, for example, hypertension, angina pectoris, heart failure, myocardial infarction , Stroke, lameness, diabetic nephropathy, diabetic retinopathy, vision loss, electrolyte abnormalities, cardiovascular diseases such as arteriosclerosis, eg central nervous system diseases such as bulimia, diabetic neuropathy, eg metabolic syndrome, Metabolic diseases such as obesity, diabetes, insulin resistance, hyperlipidemia, hypercholesterolemia, hypertriglyceremia, dyslipidemia, nonalcoholic fatty liver, abnormal hormone secretion, gout, fatty liver, For example, menstrual disorders, reproductive system diseases such as sexual dysfunction, liver dysfunction, pancreatitis, cholecystitis, gastrointestinal system diseases such as gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), sleep apnea syndrome Which respiratory diseases, infectious diseases caused by bacteria, fungi, parasites, malignant neoplasms, arthritis, can serve as a treatment agent, such as inflammatory diseases such as skin ulcers.

  One aspect of the present invention is to administer a therapeutically or prophylactically effective amount of Compound (I) according to the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. It is to provide a method of treating or preventing a disease, illness or condition resulting from modulation of LCE.

  Another aspect of the present invention is that a therapeutically or prophylactically effective amount of a compound (I) according to the present invention or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. By providing a therapeutic or preventive method for metabolic syndrome, fatty liver, hyperlipidemia, dyslipidemia, nonalcoholic fatty liver disease, obesity, diabetes, bulimia, malignant neoplasms or infectious diseases is there.

  Another aspect of the present invention is a metabolic method comprising administering to a subject in need thereof a therapeutically effective amount of a compound (I) according to the present invention or a pharmaceutically acceptable salt thereof. It is to provide a treatment for syndrome, fatty liver, hyperlipidemia, obesity, diabetes, bulimia, malignant neoplasm or infectious disease.

  Another aspect of the present invention is that a therapeutically or prophylactically effective amount of a compound (I) according to the present invention or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. It is to provide a method for treating or preventing diabetes.

  Another aspect of the present invention is that a therapeutically or prophylactically effective amount of a compound (I) according to the present invention or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. It is to provide a method for treating or preventing obesity.

  Another aspect of the present invention is that a therapeutically or prophylactically effective amount of a compound (I) according to the present invention or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. Overeating, bulimia, high blood pressure, elevated plasma insulin concentration, insulin resistance, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, renal cancer, osteoarthritis, obstructive sleep Apnea, heart disease, abnormal heart rhythm, arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary, craniopharyngioma, metabolic syndrome, insulin resistance syndrome, sexual function and Reproductive dysfunction, infertility, hypogonadism, hirsutism, obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), inflammation, systemic vasculitis, arteriosclerosis, hypercholesterolemia, high uric acid , Back pain, inflammation, systemic vasculitis, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, constipation, irritable bowel syndrome, inflammatory bowel syndrome, cardiac hypertrophy and left The object is to provide a method for treating or preventing obesity-related diseases selected from the group consisting of ventricular hypertrophy.

  Another aspect of the present invention is that a therapeutically or prophylactically effective amount of a compound (I) according to the present invention or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. It is to provide a method for treating or preventing hyperlipidemia or dyslipidemia.

  Another aspect of the present invention is that a therapeutically or prophylactically effective amount of a compound (I) according to the present invention or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. It is to provide a method of caloric intake.

  Another aspect of the present invention is that a therapeutically or prophylactically effective amount of a compound (I) according to the present invention or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. It is to provide a method for reducing food intake.

  Another aspect of the present invention is that a therapeutically or prophylactically effective amount of a compound (I) according to the present invention or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. It is to provide a method for increasing satiety.

  Another aspect of the present invention is that a therapeutically or prophylactically effective amount of a compound (I) according to the present invention or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. It is to provide a method for reducing appetite.

  The present invention also provides therapeutically or prophylactically effective compounds (I) or pharmaceutically acceptable salts thereof according to the present invention for other drugs known to be useful for the treatment or prevention of the condition. The present invention relates to a method for treating or preventing obesity comprising administering in combination with an amount.

  The present invention also provides therapeutically or prophylactically effective compounds (I) or pharmaceutically acceptable salts thereof according to the present invention for other drugs known to be useful for the treatment or prevention of the condition. The present invention relates to a method for treating or preventing diabetes comprising administering in combination with an amount. The present invention also provides therapeutically or prophylactically effective compounds (I) or pharmaceutically acceptable salts thereof according to the present invention for other drugs known to be useful for the treatment or prevention of the condition. The present invention relates to a method for treating or preventing hyperlipidemia or dyslipidemia comprising administration in combination with an amount.

Another aspect of the present invention is to provide a pharmaceutical composition comprising the compound (I) according to the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Yet another aspect of the present invention relates to compound (I) according to the present invention or a pharmaceutically acceptable salt thereof for use as a medicament.

  Still another aspect of the present invention is the compound (I) according to the present invention for the manufacture of a medicament useful for the treatment, prevention, or suppression of a disease caused by LCE in a subject in need thereof, or a pharmacy thereof Relating to the use of chemically acceptable salts.

  Yet another aspect of the present invention is the metabolic syndrome, hyperlipidemia, dyslipidemia, non-alcoholic fatty liver, obesity, diabetes, bulimia, malignant neoplasm or infection of the subject in need thereof It relates to the use of compound (I) according to the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment or prevention of sexually transmitted diseases.

  Yet another aspect of the present invention is the compound (I) according to the present invention for the manufacture of a medicament useful for the treatment or prevention of obesity in a subject in need thereof, or a pharmaceutically acceptable product thereof. Relates to the use of salt. Yet another aspect of the present invention is the compound (I) of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment or prevention of diabetes in a subject in need thereof. About the use of. Yet another aspect of the present invention is the compound (I) according to the present invention for the manufacture of a medicament useful for the treatment or prevention of hyperlipidemia or dyslipidemia in a subject in need thereof, or those The use of a pharmaceutically acceptable salt.

In still another aspect of the present invention, there is provided a therapeutically effective amount of compound (I) according to the present invention or a pharmaceutically acceptable salt thereof, an insulin resistance ameliorating agent, an insulin analog, a sulfonylurea, α-glucosidase inhibitor, dipeptidyl peptidase 4 (DPP-4 or DP-IV) inhibitor, glucagon-like peptide 1 (GLP-1) agonist, HMG-CoA reductase inhibitor, serotonin-like substance, β3-adrenergic receptor Body agonist, neuropeptide Y1 antagonist, neuropeptide Y2 agonist, neuropeptide Y5 antagonist, pancreatic lipase inhibitor, cannabinoid CB1 receptor antagonist or inverse agonist, melanin-concentrating hormone receptor agonist, melanocortin 4 receptor agonist Drugs, bombesin receptor subtype 3 agonists, ghrelin antagonists, PYY, PY _3-36 and to the use of drugs or therapeutically effective amount of their pharmaceutically acceptable salts are selected from the group consisting of NK-1 antagonist, obesity in a subject in need thereof, Diabetes And the above use for the manufacture of a medicament useful for the treatment, control or prevention of diabetes related diseases or obesity related diseases.

In still another aspect of the present invention, there is provided a therapeutically effective amount of compound (I) according to the present invention or a pharmaceutically acceptable salt thereof, an insulin resistance ameliorating agent, an insulin analog, a sulfonylurea, α-glucosidase inhibitor, dipeptidyl peptidase 4 (DPP-4 or DP-IV) inhibitor, glucagon-like peptide 1 (GLP-1) agonist, HMG-CoA reductase inhibitor, serotonin-like substance, β3-adrenergic receptor Body agonist, neuropeptide Y1 antagonist, neuropeptide Y2 agonist, neuropeptide Y5 antagonist, pancreatic lipase inhibitor, cannabinoid CB1 receptor antagonist or inverse agonist, melanin-concentrating hormone receptor agonist, melanocortin 4 receptor agonist Drugs, bombesin receptor subtype 3 agonists, ghrelin antagonists, PYY, PY _3-36 and NK-1 drugs selected from the group consisting of antagonist or a therapeutically effective amount of obesity of their pharmaceutically acceptable salts, diabetes, treating or preventing diabetes-related diseases or obesity-related disorders The present invention relates to the use of an effective amount of the compound (I) according to the present invention or a pharmaceutically acceptable salt thereof and the effective amount of the above-mentioned drug simultaneously or separately.

In still another aspect of the present invention, there is provided a therapeutically effective amount of compound (I) according to the present invention or a pharmaceutically acceptable salt thereof, an insulin resistance ameliorating agent, an insulin analog, a sulfonylurea, α-glucosidase inhibitor, dipeptidyl peptidase 4 (DPP-4 or DP-IV) inhibitor, glucagon-like peptide 1 (GLP-1) agonist, HMG-CoA reductase inhibitor, serotonin-like substance, β3-adrenergic receptor Body agonist, neuropeptide Y1 antagonist, neuropeptide Y2 agonist, neuropeptide Y5 antagonist, pancreatic lipase inhibitor, cannabinoid CB1 receptor antagonist or inverse agonist, melanin-concentrating hormone receptor agonist, melanocortin 4 receptor agonist Drugs, bombesin receptor subtype 3 agonists, ghrelin antagonists, PYY, PY Consisting _3-36 and drug or therapeutically effective amount of their pharmaceutically acceptable salts are selected from the group consisting of NK-1 antagonist, simultaneous obesity, diabetes, diabetes-related disease or obesity-related diseases , Products as combinations for separate or sequential use.

In yet another aspect of the present invention, there is provided a therapeutically effective amount of Compound (I) according to the present invention or a pharmaceutically acceptable salt thereof,
Use of a therapeutically effective amount of a drug selected from the group consisting of simvastatin, mevastatin, ezetimibe, atorvastatin, sitagliptin, metformin, sibutramine, orlistat, Qnexa (trade name) and phentermine, or a pharmaceutically acceptable salt thereof And relates to the above use for the manufacture of a medicament useful for the treatment, control or prevention of obesity, diabetes, diabetes related diseases or obesity related diseases in a subject in need thereof.

  When the compound according to the present invention is used clinically, it can be administered after various preparations by adding a pharmaceutically acceptable additive according to the administration form. As the additive at that time, various additives that are usually used in the pharmaceutical field can be used. For example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, methylated cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, Corn starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, Hardened castor oil, polyvinylpyrrolidone, magnesium stearate, palmitooleic acid, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, Pyrene glycol, polyalkylene glycol, cyclodextrin or hydroxypropyl cyclodextrin and the like.

  Examples of dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories; or liquid preparations such as syrups, elixirs or injections, etc. These can be prepared according to conventional methods in the pharmaceutical field. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. In particular, in the case of injections, they may be dissolved or suspended in physiological saline or glucose solution as necessary, and buffering agents and preservatives may be added.

  The compounds according to the present invention are effective for animals and plants including humans or other mammals that require treatment with the compounds. The mammal is preferably a human and may be male or female. Examples of mammals other than humans include pets such as dogs and cats. The compound according to the present invention is also effective against obesity such as dogs and cats or diseases related to obesity. Whether or not treatment with the compound is required can be readily determined by a regular physician, veterinarian or clinician.

  When the compound according to the present invention is used, for example, in a clinical setting, the dose and the number of administrations vary depending on the sex, age, weight, degree of symptoms of the patient, and the type and range of the intended treatment effect. In the case of oral administration, 0.01 to 100 mg / kg, preferably 0.03 to 1 mg / kg per adult day, is divided into 1 to several times, and in the case of parenteral administration, 0.001 to 10 mg / kg. It is preferable to administer kg, preferably 0.001 to 0.1 mg / kg, more preferably 0.01 to 0.1 mg / kg divided into 1 to several times.

  For oral administration, 1.0-1000 mg of active ingredient, especially 1.0, 5.0, 10.0, 15.0, 20 to adjust the dosage to the condition of the patient being treated 0.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0 800.0, 900.0 and 1000.0 mg tablets containing 1000.0 mg of the active ingredient are preferred. The compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

  The compounds according to the invention are applied for the treatment or prevention of obesity and / or diabetes and / or hyperlipidemia and / or dyslipidemia and / or non-alcoholic fatty liver, or other diseases In this case, when the daily dose of the compound of the present invention is about 0.1 mg to about 100 mg per kg body weight of the animal, it is more preferable to administer a single dose or 2 to 6 divided doses per day, or gradually. Satisfactory results can generally be obtained when using a releasable formulation. For many large mammals, the total daily dose is from about 1.0 mg to about 1000 mg, preferably from about 1 mg to about 50 mg. For a 70 kg adult, the total daily dose will usually be from about 7 mg to about 350 mg. This dosage regimen can be adjusted to provide the best therapeutic effect.

  Ordinary physicians, veterinarians or clinicians can easily determine and handle the effective amount of drug needed to treat, prevent, prevent, inhibit or stop disease progression.

  These preparations can contain the compound according to the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 60% by weight of the total drug. These formulations may also contain other therapeutically effective compounds.

  The compounds according to the present invention include cardiovascular diseases such as hypertension, angina pectoris, heart failure, myocardial infarction, stroke, lameness, diabetic nephropathy, diabetic retinopathy, vision loss, electrolyte abnormalities, arteriosclerosis, such as bulimia Central nervous system diseases such as diabetic neuropathy, eg metabolic syndrome, obesity, diabetes, insulin resistance, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, nonalcoholic fat Metabolic diseases such as liver, hormonal secretion abnormalities, gout, fatty liver, reproductive system diseases such as menstrual disorders, sexual dysfunction, liver dysfunction, pancreatitis, cholecystitis, gastrointestinal tract diseases such as gastroesophageal reflux, low obesity Respiratory diseases such as ventilation syndrome (Pickwick syndrome), sleep apnea syndrome, infectious diseases caused by bacteria, fungi, and parasites, malignant neoplasms, arthritis, inflammatory diseases such as skin ulcers, and other diseases It can be used in combination with other agents useful for location. The individual components of such a combination can be administered in divided or single formulations at different times or simultaneously during the treatment period. Thus, the present invention should be construed to include all simultaneous or timed administrations, and administration in the present invention should be construed as such. The range of combinations of the compounds of the present invention with other agents useful for the treatment of the above-mentioned diseases includes, in principle, combinations with any pharmaceutical preparations useful for the treatment of the above-mentioned diseases.

Such combinations include combinations of the composition of the present invention not only with one other active substance, but also with two or more other active substances. There are many examples of combinations of the composition of the present invention with one, two or more activators selected from the above therapeutic agents. For example, for the purpose of treatment / management / prevention of metabolic syndrome, one, two or more activators selected from the composition of the present invention and a hyperlipidemic agent, a lipid-reducing agent and an anti-diabetic agent The combination with is beneficial. In particular, in addition to anti-diabetic drugs and / or anti-hyperlipidemic agents or lipid-reducing agents, compositions comprising anti-obesity agents and anti-hypertensive agents have a synergistic effect on the treatment, management or prevention of metabolic syndrome To do.
Examples of drugs combined with this drug include ACAT inhibitor, α-procker, aldose reductase inhibitor, α-amylase inhibitor, angiotensin converting enzyme inhibitor, angiotensin receptor antagonist, anion exchange resin, appetite suppressant, antioxidant Agent, antiplatelet agent, beta blocker, biguanide agent, calcium antagonist, CB1 receptor inverse agonist / antagonist, CETP inhibitor, cholesterol absorption inhibitor, DGAT inhibitor, DP-IV inhibitor, diuretic, eicosapentaenoic acid , Endothelin antagonist, FLAP inhibitor, FXR modulator, ghrelin antagonist, GLP-1 agonist, GLP-1 secretion agent, glucagon antagonist, glucokinase activator, glucocorticoid receptor ligand, α-glycosidase inhibitor, GPAT inhibition Agent, histamine 3 receptor ligands, HMG-CoA reductase inhibitors, HSD inhibitors, insulin and analogs thereof, kinase inhibitors such as VEGF inhibitors and PDGF inhibitors, leptin, lipase inhibitors, 5-LO inhibitors, LXR ligands, Melanocortin agonist, MCH antagonist, MTTP inhibitor, orexin antagonist, opioid antagonist, neuropeptide Y antagonist, nicotinic acid agonist, PPAR ligand, PTP-1B inhibitor, SCD-1 inhibitor, serotonin transporter inhibitor, SGLT inhibitors, SUR ligands, thyroid hormone agonists, UCP activators, VPAC receptor agonists and the like.

  The compound according to the present invention has an excellent LCE inhibitory action and is useful as a therapeutic agent for various diseases associated with LCE, such as cardiovascular diseases, nervous system diseases, metabolic diseases, reproductive diseases, gastrointestinal diseases. It is.

  EXAMPLES The present invention will be described more specifically with reference to examples and production examples below, but the present invention is not limited by these.

In the thin layer chromatography of Examples and Production Examples, Silica gel ₆₀ F ₂₅₄ (Merck) was used as a plate, and a UV detector was used as a detection method. As column silica gel, Wakogel ^™ C-300 or C-200 (Wako Pure Chemical Industries), FLASH + cartridge (Biotage) or Chromatorex (FUJI SILYSIA CHEMICAL) was used. MS spectra were measured using ZQ2000 (Waters). When NMR spectra are measured with a deuterated dimethyl sulfoxide solution, dimethyl sulfoxide is used as an internal standard, and a JNM-AL400 (JEOL), Mercury 400 (400 MHz; Varian), or Inova 400 (400 MHz; Varian) type spectrometer is used. The total δ value was expressed in ppm.
The meanings of the abbreviations in the NMR measurement are shown below.
s: singlet d: doublet dd: double doublet t: triplet dt: double triplet q: quartet m: multiplet br: broad J: coupling constant Hz: hertz DMSO-d ₆ : heavy dimethyl sulfoxide

Example 1
(6-Chloro-4-cyclopropyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-4-yl) methyl (4-fluorophenyl) carbamate 1) (2-amino-5- Synthesis of chlorophenyl) (cyclopropyl) methanone 2-Amino-5-chlorobenzonitrile (500 mg, 3.28 mmol) was dissolved in THF (10 mL) and cyclopropylmagnesium bromide (0.5 M, THF solution, 26.4 mL). Was added dropwise to the reaction solution stirred at 0 ° C. The reaction solution was heated and stirred at 80 ° C. overnight, then ice-cooled, and 2N hydrochloric acid was added under ice-cooling. After stirring the reaction solution at room temperature for 2 hours, the solution was diluted with ethyl acetate and neutralized with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3/1) to obtain (2-amino-5-chlorophenyl) (cyclopropyl) methanone (453 mg, 83%) as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.98-1.03 (2H, m), 1.16-1.20 (2H, m), 2.54-2.60 (1H, m) , 6.61 (1H, d, J = 8.8 Hz), 7.21 (1H, dd, J = 8.8, 2.4 Hz), 7.92 (1H, d, J = 2.4 Hz).
2) Synthesis of 6-chloro-4-cyclopropyl-4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (2-amino-5-chlorophenyl) (cyclopropyl) methanone ( 450 mg, 2.30 mmol) was dissolved in THF (5 mL), and vinylmagnesium bromide (1.0 M THF solution, 5.7 mL) was added dropwise to the reaction solution stirred at 0 ° C. The reaction solution was stirred at room temperature overnight, and a saturated aqueous ammonium chloride solution was added to the solution. The solution was diluted with ethyl acetate, the organic layer was separated, washed with saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was dissolved in THF (5 mL), and 1,1-carbonyldiimidazole (CDI) (745 mg) was added at room temperature. After stirring the reaction solution at room temperature for 2 hours, water was added to the reaction solution under ice cooling. The solution was diluted with ethyl acetate and saturated aqueous ammonium chloride was added. The organic layer was separated, washed with saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2) to give 6-chloro-4-cyclopropyl-4-vinyl-1,4-dihydro-2H-3,1-benzoxazine-2- On (610 mg) was obtained quantitatively as a pale white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.30-0.36 (1H, m), 0.44-0.58 (2H, m), 0.65-0.72 (1H, m), 1.50-1.57 (1H, m), 5.10 (1H, dd, J = 17.1, 1.0 Hz), 5.27 (1H, dd, J = 10.7, 1 .0Hz), 5.90 (1H, dd, J = 17.1, 10.7 Hz), 6.90 (1H, d, J = 8.3 Hz), 7.36 (1H, dd, J = 8. 5, 2.2 Hz), 7.42 (1 H, d, J = 2.0 Hz), 10.40 (1 H, s).
3) Synthesis of 6-chloro-4-cyclopropyl-4- (hydroxymethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one 6-chloro-4-cyclopropyl-4-vinyl -1,4-Dihydro-2H-3,1-benzoxazin-2-one (590 mg, 2.36 mmol) was dissolved in dichloromethane (2.5 mL) and methanol (2.5 mL), and −78 ° C. under a stream of ozone. Was stirred. After confirming the disappearance of the raw materials by thin layer chromatography, the ozone stream was changed to a nitrogen stream and stirred for 5 minutes. The reaction solution was warmed to 0 ° C. and sodium borohydride (26.8 mg, 7.1 mmol) was added. After stirring the reaction solution at 0 ° C. for 30 minutes, acetone was added to stop the reaction. After distilling off the solvent under reduced pressure, water (50 mL) and 1N hydrochloric acid were added to the residue to adjust to pH = 4, followed by stirring at room temperature. The resulting white solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the desired product (487 mg, 81%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.09-0.15 (1H, m), 0.29-0.35 (1H, m), 0.37-0.49 (2H, m), 1.33-1.40 (1H, m), 3.69 (1H, d, J = 11.7 Hz), 3.85 (1H, d, J = 11.7 Hz), 6.82 ( 1H, d, J = 8.3 Hz), 7.28 (1H, dd, J = 8.3, 2.4 Hz), 7.37 (1H, d, J = 2.4 Hz).
4) Synthesis of (6-chloro-4-cyclopropyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-4-yl) methyl (4-fluorophenyl) carbamate 6-chloro-4 -Cyclopropyl-4- (hydroxymethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one (30 mg, 0.124 mmol) and TEA (20.7 μL, 0.15 mmol) in THF ( 0.5 mL), 1-fluorophenyl-4-isocyanate (17 μL, 0.15 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature overnight, the solvent was evaporated under reduced pressure, the residue was filtered off, and washed with chloroform. After concentrating the mother liquor, the residue was purified by thin layer silica gel column chromatography (ethyl acetate / hexane = 1/1) and crystallized from ethyl acetate-heptane to obtain the desired product (9.5 mg, 20%). Obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.12-0.18 (1H, m), 0.23-0.29 (1H, m), 0.44-0.55 (2H, m), 1.39-1.46 (1H, m), 4.51 (1H, d, J = 12.2 Hz), 4.76 (1H, d, J = 12.2 Hz), 6.88 ( 1H, d, J = 8.3 Hz), 7.10 (2H, t, J = 8.3 Hz), 7.34 (1H, dd, J = 8.3, 2.4 Hz), 7.38-7 .48 (2H, brm), 7.51 (1H, d, J = 2.4 Hz).

Example 2
(4-Methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-4-yl) methyl (4-fluorophenyl) carbamate 2-aminobenzonitrile, methylmagnesium bromide, 1-fluorophenyl The title compound was obtained by the method according to Example 1 using -4-isocyanate as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.64 (3H, s), 4.31 (1H, d, J = 12.2 Hz), 4.55 (1H, d, J = 12. 2 Hz), 6.89 (1 H, d, J = 8.8 Hz), 7.04 (1 H, d, J = 8.8 Hz), 7.05-7.15 (2 H, m), 7.27 ( 1H, t, J = 8.8 Hz), 7.32 (1H, d, J = 8.8 Hz), 7.44 (2H, brs)

Example 3
[6-chloro-2-oxo-4-phenyl-1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-fluorophenyl) carbamate 2-amino-5-chlorobenzonitrile, The title compound was obtained by the method according to Example 1 using phenylmagnesium bromide and 1-fluorophenyl-4-isocyanate as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.70 (1H, d, J = 12.2 Hz), 4.94 (1H, d, J = 12.2 Hz), 6.94 (1H, d, J = 8.8 Hz), 7.09-7.13 (2H, m), 7.32-7.34 (2H, m), 7.38-7.46 (6H, m), 7. 76 (1H, d, J = 2.4 Hz).

Example 4
[6-Chloro-2-oxo-4-phenyl-1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (pyridin-3-yl) carbamate 2-amino-5-chlorobenzonitrile , Phenylmagnesium bromide and 3-isocyanatepyridine were used as raw materials to obtain the title compound by the method according to Example 1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.74 (1H, d, J = 12.7 Hz), 4.97 (1H, d, J = 12.7 Hz), 6.94 (1H, d, J = 8.3 Hz), 7.29-7.34 (3H, m), 7.37-7.46 (4H, m), 7.78 (1H, d, J = 2.0 Hz), 7.87 (1H, brs), 8.21 (1H, dd, J = 4.4, 1.5 Hz), 8.61 (1H, brs).

Example 5
[6-chloro-4-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-fluorophenyl) carbamate 2-amino-5-chlorobenzonitrile, The title compound was obtained by the method according to Example 1 using methylmagnesium bromide and 1-fluorophenyl-4-isocyanate as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.64 (3H, s), 4.33 (1H, d, J = 12.2 Hz), 4.57 (1H, d, J = 12. 2 Hz), 6.90 (1 H, d, J = 8.8 Hz), 7.11 (2 H, t, J = 8.8 Hz), 7.33 (1 H, dd, J = 8.8, 2.4 Hz) ), 7.42 (2H, brs), 7.46 (1H, d, J = 2.4 Hz), 9.73 (1H, brs).

Example 6
[6-chloro-4-isopropyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-fluorophenyl) carbamate 2-amino-5-chlorobenzonitrile, The title compound was obtained by the method according to Example 1 using isopropylmagnesium bromide and 1-fluorophenyl-4-isocyanate as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.80 (3H, d, J = 6.8 Hz), 0.97 (3H, d, J = 6.8 Hz), 2.28 (1H, q, J = 6.8 Hz), 4.51 (1H, d, J = 12.2 Hz), 4.69 (1H, d, J = 12.2 Hz), 6.86 (1H, d, J = 8) .3 Hz), 7.05-7.12 (2H, brm), 7.31 (1H, dd, J = 8.3, 2.0 Hz), 7.36-7.43 (2H, brm), 7 .44 (1H, d, J = 2.0 Hz).

Example 7
[6-chloro-4-ethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-fluorophenyl) carbamate 2-amino-5-chlorobenzonitrile, The title compound was obtained by the method according to Example 1 using ethylmagnesium bromide and 1-fluorophenyl-4-isocyanate as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.79 (3H, t, J = 7.3 Hz), 1.91-2.08 (2H, m), 4.35 (1H, d, J = 12.2 Hz), 4.58 (1 H, d, J = 12.2 Hz), 6.88 (1 H, d, J = 8.8 Hz), 7.10 (2 H, t, J = 8.8 Hz) ), 7.32 (1H, dd, J = 8.8, 2.4 Hz), 7.36-7.46 (2H, brm), 7.44 (1H, d, J = 2.4 Hz).

Example 8
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl-pyrrolidine-1-carboxylate 6-chloro-4- A method according to Example 1 using (hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and pyrrolidine-1-carbonyl chloride as raw materials Gave the title compound.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.64-1.85 (4H, m), 3.03-3.09 (1H, m), 3.18-3.24 (1H, m) , 3.33-3.37 (2H, m), 4.59 (1H, d, J = 12.2 Hz), 4.81 (1H, d, J = 12.2 Hz), 6.89 (1H, d, J = 8.8 Hz), 7.34 (1H, brs), 7.36 (1H, dd, J = 8.8, 2.4 Hz), 9.36 (1H, brs).

Example 9
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-methoxyphenyl) carbamate 6-chloro-4- Using (hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-methoxyphenyl isocyanate as raw materials, a method according to Example 1 was used. The title compound was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.71 (3H, s), 4.79 (1H, d, J = 12.7 Hz), 5.04 (1H, d, J = 12. 7 Hz), 6.84-6.86 (2H, brm), 7.00 (1H, dd, J = 8.8, 1.0 Hz), 7.32 (2H, s), 7.52-7. 54 (1H, m), 7.75 (1H, s), 9.60-9.63 (1H, brm).

Example 10
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-phenoxyphenyl) carbamate 6-chloro-4- Using (hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-phenoxyphenyl isocyanate as raw materials, a method according to Example 1 was used. The title compound was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.83 (1H, d, J = 12.2 Hz), 5.07 (1H, d, J = 12.2 Hz), 6.93-7. 02 (5H, m), 7.09 (1H, dd, J = 7.3, 7.3 Hz), 7.35 (2H, dd, J = 8.8, 7.3 Hz), 7.44 (2H , Brs), 7.53 (1H, dd, J = 8.8, 2.2 Hz), 7.76 (1H, brs).

Example 11
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl [4- (benzyloxy) phenyl] carbamate 6-chloro Example using -4- (hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and 4- (benzyloxy) phenyl isocyanate as raw materials The title compound was obtained by the method according to 1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.79 (1H, d, J = 12.2 Hz), 5.04 (2H, s), 5.04 (1H, d, J = 12. 2 Hz), 6.92-6.95 (2H, brm), 7.00 (1H, d, J = 8.8 Hz), 7.30-7.44 (7H, m), 7.52 (1H, dd, J = 8.8, 2.2 Hz), 7.73-7.75 (1H, brm).

Example 12
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-fluorophenyl) carbamate 6-chloro-4- In accordance with Example 1, using (hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and (4-fluorophenyl) isocyanate as raw materials The title compound was obtained by the method.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.82 (1H, d, J = 12.2 Hz), 5.07 (1H, d, J = 12.2 Hz), 7.00 (1H, d, J = 8.8 Hz), 7.10-7.15 (2H, brm), 7.44 (2H, brs), 7.53 (1H, dd, J = 8.8, 2.4 Hz), 7.76 (1H, brs).

Example 13
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-chlorophenyl) carbamate 6-chloro-4- ( Hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and (4-chlorophenyl) isocyanate as raw materials, and a method according to Example 1 The title compound was obtained.
¹ H-NMR (400 MHz, CD ₃ OD) δ: 4.77 (1H, d, J = 12.3 Hz), 5.04 (1H, d, J = 12.3 Hz), 6.94 (1H, d , J = 8.6 Hz), 7.23 (2H, d, J = 8.2 Hz), 7.37 (2H, brs), 7.44 (1H, dd, J = 8.6, 2.2 Hz) 7.56 (1H, brs).

Example 14
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (2,4-difluorophenyl) carbamate 6-chloro- Examples using 4- (hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and (2,4-difluorophenyl) isocyanate as raw materials The title compound was obtained by the method according to 1.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.74 (1H, d, J = 12.7 Hz), 4.92 (1H, d, J = 12.7 Hz), 6.72-6.89 ( 2H, m), 6.85 (1H, d, J = 8.8 Hz), 7.32 (1H, brs), 7.39 (1H, dd, J = 8.8, 2.0 Hz), 7. 95 (1H, brs), 8.31 (1H, s).

Example 15
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (3-fluorophenyl) carbamate 6-chloro-4- In accordance with Example 1, using (hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and (3-fluorophenyl) isocyanate as raw materials The title compound was obtained by the method.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.85 (1H, d, J = 12.2 Hz), 5.09 (1 H, d, J = 12.2 Hz), 6.84 (1H, td, J = 8.8, 2.0 Hz), 7.01 (1H, d, J = 8.3 Hz), 7.19-7.23 (1H, brm), 7.31 (2H, dd, J = 15.6, 8.3 Hz), 7.54 (1H, dd, J = 8.8, 2.0 Hz), 7.77 (1H, s).

Example 16
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-pyrido [2,3-d] [1,3] oxazin-4-yl] methyl (4-fluorophenyl) ) Carbamate 1) Synthesis of 1- (2-amino-5-chloropyridin-3-yl) -2,2,2-trifluoroethanone N- (5-Chloro-2-pyridinyl) -2,2-dimethylpropane Amide (20.0 g, 94.0 mmol) and TMEDA (12.0 g, 103 mmol) were dissolved in t-butyl methyl ether (150 mL), and the reaction solution was stirred at −20 ° C. under n-butyl lithium (2.66 M). Hexane solution, 88.3 mL) was added dropwise. The reaction solution was stirred at 0 ° C. for 2 hours, cooled to −78 ° C., and ethyl trifluoroacetate (16.8 mL, 140 mmol) was added. The reaction solution was heated to 0 ° C. and stirred for 3 hours, and then water and 2N hydrochloric acid were sequentially added to adjust the reaction solution to about pH = 9. The solution was diluted with ethyl acetate, the organic layer was separated, and the solvent was distilled off under reduced pressure. Acetic acid (60 mL), concentrated hydrochloric acid (20 mL) and water (40 mL) were added to the residue, and the solution was stirred with heating at 100 ° C. for 10 hr. After cooling the solution to room temperature, the resulting solid was collected by filtration and washed with ethyl acetate. The obtained solid and sodium acetate (7.64 g) were mixed in water (15 mL) and t-butyl methyl ether (70 mL), and the solution was stirred at room temperature for 30 minutes. The solution was diluted with ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain the desired product (10.1 g, 47.8%) as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.32 (2H, brs), 7.54 (1H, brs), 8.15 (1H, brs).
2) [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-pyrido [2,3-d] [1,3] oxazin-4-yl] methyl (4- Synthesis of fluorophenyl) carbamate.
Using 1- (2-amino-5-chloropyridin-3-yl) -2,2,2-trifluoroethanone and (4-fluorophenyl) isocyanate as raw materials, the title compound was prepared according to the method of Example 1. Obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.86 (1H, d, J = 12.2 Hz), 5.05 (1H, d, J = 12.2 Hz), 7.12-7. 14 (2H, brm), 7.42-7.44 (2H, brm), 8.37 (1H, d, J = 2.4 Hz), 8.50 (1H, d, J = 2.4 Hz).

Example 17
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-pyrido [2,3-d] [1,3] oxazin-4-yl] ethyl (4-fluorophenyl) ) Carbamate Using 2-amino-5-chloropyridine, ethyl trifluoroacetate, allylmagnesium bromide and (4-fluorophenyl) isocyanate as raw materials, the title compound was obtained by a method according to Example 1 and Example 16.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.97-3.04 (1H, m), 3.27-3.38 (1H, m), 4.18-4.30 (2H, m), 7.09 (2H, dd, J = 8.8, 8.8 Hz), 7.33 (2H, brs), 8.23 (1H, brs), 8.34 (1H, d, J = 2.0 Hz).

Example 18
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl [4- (methylsulfonyl) phenyl] carbamate 6-chloro Example using -4- (hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and 4- (methylsulfonyl) phenyl isocyanate as raw materials The title compound was obtained by the method according to 1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.15 (3H, s), 4.87 (1H, d, J = 12.2 Hz), 5.11 (1H, d, J = 12. 2 Hz), 7.00 (1 H, d, J = 8.8 Hz), 7.53 (1 H, dd, J = 8.8, 2.4 Hz), 7.66 (2 H, d, J = 8.8 Hz) ), 7.76 (1H, s), 7.83 (2H, d, J = 8.8 Hz).

Example 19
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (pyridin-3-yl) carbamate 6-chloro-4 Using-(hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-isocyanatepyridine as raw materials, the method according to Example 1 was used. The title compound was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.84 (1H, d, J = 12.2 Hz), 5.08 (1H, d, J = 12.2 Hz), 6.99 (1H, d, J = 8.8 Hz), 7.32 (1H, brs), 7.51 (1H, dd, J = 8.8, 2.2 Hz), 7.75 (1H, s), 7.87 ( 1H, brs), 8.23 (1H, dd, J = 4.9, 1.5 Hz), 8.59 (1H, brs).

Example 20
2-[({[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methoxy} carbonyl) amino] pyridinium trifluoro Acetate Examples using 6-chloro-4- (hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and 2-isocyanatepyridine as raw materials The title compound was obtained by the method according to 1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.80 (1H, d, J = 12.2 Hz), 5.08 (1H, d, J = 12.2 Hz), 7.00 (1H, d, J = 8.3 Hz), 7.05-7.08 (1H, m), 7.53 (1H, dd, J = 8.3, 2.4 Hz), 7.69-7.72 (1H) M), 7.74-7.78 (2H, m), 8.24-8.26 (1H, m).

Example 21
[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (cyclopentyl) carbamate 6-chloro-4- (hydroxymethyl) ) -4- (Trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and cyclopentyl isocyanate were used as raw materials, and the title compound was obtained by the method according to Example 1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.28-1.57 (6H, m), 1.68-1.76 (2H, m), 3.70-3.75 (1H, m), 4.62 (1H, d, J = 12.2 Hz), 4.92 (1H, d, J = 12.2 Hz), 6.97 (1H, d, J = 8.8 Hz), 7. 38 (1H, d, J = 6.8 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.63 (1H, s).

Example 22
[8-methoxy-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-fluorophenyl) carbamate 2-methoxyaniline, tri The title compound was obtained by a method according to Example 1 and Example 16 using ethyl fluoroacetate and (4-fluorophenyl) isocyanate as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.84 (3H, s), 4.75 (1H, d, J = 12.2 Hz), 5.01 (1H, d, J = 12. 2 Hz), 7.10-7.14 (5H, m), 7.41-7.46 (2H, brm).

Example 23
[6-Chloro-1-methyl-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-fluorophenyl) carbamate 1) Synthesis of 6-chloro-4- (trifluoromethyl) -4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one 4-chloroaniline, ethyl trifluoroacetate, vinylmagnesium bromide Using the starting material, the title compound was obtained by the method according to Example 1 and Example 16.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 5.66 (1H, d, J = 16.8 Hz), 5.69 (1H, d, J = 11.0 Hz), 6.64 (1H, dd, J = 16.8, 11.0 Hz), 7.00 (1H, d, J = 8.8 Hz), 7.51 (1H, dd, J = 8.8, 2.4 Hz), 7.61 (1H, d, J = 2.4 Hz), 10.99 (1H, s).
2) Synthesis of 6-chloro-1-methyl-4- (trifluoromethyl) -4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one 6-chloro-4- (tri To a stirred solution of fluoromethyl) -4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (100 mg, 0.36 mmol) in DMF (1 mL) at 0 ° C., sodium hydride ( 60%, 29 mg, 0.72 mmol) was added. After stirring at 0 ° C. for 30 minutes, methyl iodide (44.8 μL, 0.72 mmol) was added dropwise. After stirring the reaction solution at room temperature overnight, water was added to the reaction solution. The solution was diluted with ethyl acetate and saturated aqueous ammonium chloride was added. The organic layer was separated, washed with saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain the desired product (107 mg, quant.) As a light brown solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.41 (3H, s), 5.66 (1H, d, J = 10.7 Hz), 5.67 (1H, d, J = 17.1 Hz) 6.18 (1H, dd, J = 17.1, 10.7 Hz), 6.94 (1H, d, J = 8.8 Hz), 7.34 (1H, d, J = 2.4 Hz), 7.42 (1H, dd, J = 8.8, 2.4 Hz).
3) [6-Chloro-1-methyl-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-fluorophenyl) carbamate Using 6-chloro-1-methyl-4- (trifluoromethyl) -4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and (4-fluorophenyl) isocyanate as raw materials The title compound was obtained by a method according to Example 1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.36 (3H, s), 4.85 (1H, d, J = 12.2 Hz), 5.10 (1H, d, J = 12. 2Hz), 7.09-7.15 (2H, m), 7.29 (1H, d, J = 8.8 Hz), 7.41-7.46 (2H, brm), 7.66 (1H, dd, J = 8.8, 2.4 Hz), 7.82 (1H, d, J = 2.4 Hz).

Example 24
[5-Methoxy-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-fluorophenyl) carbamate 3-methoxyaniline, tri The title compound was obtained by a method according to Example 1 and Example 16 using ethyl fluoroacetate and (4-fluorophenyl) isocyanate as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.84 (3H, s), 4.75 (1H, d, J = 12.2 Hz), 5.01 (1H, d, J = 12. 2Hz), 7.08-7.15 (5H, m), 7.44 (2H, brs).

Example 25
[6-Fluoro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (4-fluorophenyl) carbamate 4-fluoroaniline, tri The title compound was obtained by a method according to Example 1 and Example 16 using ethyl fluoroacetate and (4-fluorophenyl) isocyanate as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.80 (1H, d, J = 12.2 Hz), 5.03 (1H, d, J = 12.2 Hz), 7.01 (1H, dd, J = 8.8, 4.9 Hz), 7.05-7.18 (2H, brm), 7.33-7.38 (1H, m), 7.44 (2H, brs), 7. 59 (1H, dd, J = 8.8, 2.4 Hz), 9.85 (1H, brs)

Example 26
[6-Fluoro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl (pyridin-3-yl) carbamate 4-fluoro The title compound was obtained by a method according to Example 1 and Example 16 using aniline, ethyl trifluoroacetate and 3-isocyanate pyridine as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.82 (1H, d, J = 12.2 Hz), 5.05 (1H, d, J = 12.2 Hz), 7.00 (1H, dd, J = 9.0, 4.6 Hz), 7.24-7.39 (2H, m), 7.60 (1H, dd, J = 9.0, 2.7 Hz), 7.85 (1H) , Brs), 8.21 (1H, dd, J = 4.6, 1.2 Hz), 8.57 (1H, brs), 10.03 (1H, brs)

Example 27
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide 1) 6- Synthesis of chloro-4- (hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one According to Example 1, a known compound (J. Org. Chem. 1998, 63, 8536) 1- (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.93 (1H, d, J = 12.2 Hz), 4.23 (1H, d, J = 12.2 Hz), 6.91 (1H, d, J = 8.3 Hz), 7.43 (1H, dd, J = 8.3, 2.2 Hz), 7.52 (1H, brs).
2) Synthesis of 4- (azidomethyl) -6-chloro-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one 6-Chloro-4- (hydroxymethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one (4.0 g, 14.2 mmol) was dissolved in chloroform (30 mL) and THF (15 mL), Under stirring at 0 ° C., 2,6-dimethylpyridine (13.2 mL, 113 mmol) and trifluoromethanesulfonic anhydride (9.6 mL, 56.8 mmol) were sequentially added. The reaction solution was stirred for 3 hours under ice cooling, and then a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution under ice cooling. The solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in DMF (50 mL) and sodium azide (1.53 g, 23.5 mmol) was added. The reaction solution was stirred at 80 ° C. overnight, returned to room temperature, and water was added to the reaction solution. The solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2) to obtain the desired product (3.47 g, 80%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.25 (1H, d, J = 14.1 Hz), 4.55 (1H, d, J = 14.1 Hz), 7.00 (1H, d, J = 8.8 Hz), 7.54 (1H, dd, J = 8.8, 2.2 Hz), 7.73 (1H, d, J = 2.2 Hz), 11.03 (1H, brs) )
3) Synthesis of [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride 4- (azidomethyl)- 6-Chloro-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one (2.59 g, 8.44 mmol) in THF (20 mL) and water (10 mL) Trimethyl phosphite (2 mL, 16.9 mmol) was added to the mixed solution at room temperature, and the reaction solution was stirred at 60 ° C. for 5 hours. The reaction solution was allowed to cool, water was added to the reaction solution, the solution was diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. To the residue was added 4N hydrochloric acid-dioxane solution (30 mL), and the mixture was stirred at 40 ° C. for 24 hours. After allowing to cool, the resulting solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the desired product (2.31 g, 86%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.57 (1H, d, J = 14.1 Hz), 4.27 (1H, d, J = 14.1 Hz), 7.01 (1H, d, J = 8.8 Hz), 7.56 (1H, dd, J = 8.8, 2.2 Hz), 7.77 (1H, d, J = 2.2 Hz), 8.44 (2H, s) ), 11.10 (1H, s)
4) Synthesis of N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide [ 6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride (2.0 g, 6.3 mmol), 4 -A solution of fluorobenzoic acid (972 mg, 6.94 mmol), hydroxybenzotriazole hydrochloride (852 mg, 6.3 mmol) and triethylamine (2.1 mL, 15.8 mmol) in DMF (20 mL) at 0 ° C. under stirring. -Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.45 g, 7.57 mmol) was added in small portions. After stirring the reaction solution at room temperature for 5 hours, water was added to the reaction solution, the solution was diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to obtain the desired product (2.1 g, 82%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.87 (1H, dd, J = 14.4, 4.4 Hz), 4.58 (1H, dd, J = 14.4, 7.6 Hz) ), 6.92 (1H, d, J = 8.3 Hz), 7.25 (2H, t, J = 9.3 Hz), 7.43-7.50 (2H, m), 7.71-7 .78 (2H, m), 8.81 (1H, dd, J = 7.6, 4.4 Hz), 10.19 (1H, s)

N-{[(4S ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide Synthesis of N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide (HPLC Optical resolution was performed with Chiralpak AD-H, n-hexane: 2-propanol = 4: 1), and the fraction eluted in the latter half was concentrated to obtain the desired product.

Example 28
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-pyrido [3,4-d] [1,3] oxazin-4-yl] methyl}- 4-Fluorobenzamide The title compound was obtained by a method according to Example 27 using 3-amino-6-chloropyridine, ethyl trifluoroacetate and 4-fluorobenzoic acid as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.07 (1H, d, J = 10.7 Hz), 4.23 (1H, d, J = 10.7 Hz), 7.36 (2H, t, J = 8.8 Hz), 7.64 (1H, s), 8.01 (2H, dd, J = 8.8, 5.4 Hz), 8.51 (1H, s), 8.65 ( 1H, s).

Example 29
N-{[2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide aniline, ethyl trifluoroacetate and benzoic acid as raw materials And the title compound was obtained by a method analogous to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.82 (1H, d, J = 14.5 Hz), 4.62 (1 H, d, J = 14.5 Hz), 6.91 (1H, d, J = 8.2 Hz), 7.05 (1H, t, J = 7.8 Hz), 7.34-7.41 (4H, m), 7.46-7.50 (1H, m), 7.64 (2H, d, J = 7.8 Hz).

Example 30
N-{[2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} pyridine-2-carboxamide aniline, ethyl trifluoroacetate and The title compound was obtained by a method according to Example 27 using pyridine-2-carboxylic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.14 (1H, d, J = 14.5 Hz), 4.39 (1H, d, J = 14.5 Hz), 6.89 (1H, d, J = 8.0 Hz), 7.08 (1H, t, J = 7.8 Hz), 7.36 (1H, t, J = 7.5 Hz), 7.50 (1H, d, J = 7) .8 Hz), 7.55-7.58 (1 H, m), 7.93-7.98 (2 H, m), 8.56 (1 H, d, J = 4.5 Hz).

Example 31
4-fluoro-N-{[2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide aniline, ethyl trifluoroacetate and 4 -The title compound was obtained by the method according to Example 27 using fluorobenzoic acid as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.78 (1H, d, J = 14.7 Hz), 4.57 (1H, d, J = 14.7 Hz), 6.87 (1H, d, J = 8.2 Hz), 7.01 (1H, t, J = 8.0 Hz), 7.20 (2H, t, J = 9.0 Hz), 7.32 (2H, t, J = 8) .2 Hz), 7.67-7.71 (2H, m).

Example 32
N- {2- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} -4-fluorobenzamide 1- The title compound was obtained by the method according to Example 27 using (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, allylmagnesium bromide and 4-fluorobenzoic acid as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.29-2.40 (1H, m), 2.70-2.80 (1H, m), 3.31 (2H, dd, J = 13.2, 6.8 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.21-7.28 (2H, m), 7.40 (1H, dd, J = 8.8) , 2.4 Hz), 7.51-7.53 (1 H, m), 7.72-7.79 (2 H, m), 8.48 (1 H, t, J = 5.6 Hz), 10.83 (1H, s)

N- {2-[(4R ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} -4 -Fluorobenzamide N- {2- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} -4-fluoro Benzamide was subjected to optical resolution with HPLC (Chiral Pack AD-H, n-hexane: 2-propanol = 3: 1), and the fraction eluted in the latter half was concentrated to obtain the desired product.

Example 33
N- {3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propyl} -4-fluorobenzamide 1- The title compound was obtained by a method according to Example 27 using (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 4-fluorobenzoic acid as raw materials. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.25-1.40 (1H, m), 1.47-1.64 (1H, m), 2.03-2.17 (1H, m), 2.54-2.64 (1H, m), 3.19-3.37 (2H, m), 6.95 (1H, d, J = 8.5 Hz), 7.24-7. 29 (2H, m), 7.48 (1H, dd, J = 8.5, 2.2 Hz), 7.60 (1H, s), 7.84-7.91 (2H, m), 8. 51 (1H, t, J = 5.6 Hz), 10.85 (1H, s)

N- {3-[(4R ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propyl} -4 -Fluorobenzamide N- {3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propyl} -4-fluoro Benzamide was subjected to optical resolution with HPLC (Chiral Pack AD-H, n-hexane: 2-propanol = 3: 1), and the fraction eluted in the latter half was concentrated to obtain the desired product.

Example 34
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -3-fluorobenzamide [6-chloro Example 27 using 2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 3-fluorobenzoic acid as raw materials The title compound was obtained by a method according to.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.87 (1H, dd, J = 14.6, 4.4 Hz), 4.57 (1H, dd, J = 14.6, 7.8 Hz) ), 6.91 (1H, d, J = 8.8 Hz), 7.32-7.39 (1H, m), 7.42-7.53 (6H, m), 8.88 (1H, dd) , J = 7.8, 4.4 Hz), 10.87 (1H, s)

Example 35
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -2-fluorobenzamide [6-chloro Example 27 Using 2-Oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 2-fluorobenzoic acid as raw materials The title compound was obtained by a method according to.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.86 (1H, dd, J = 14.4, 4.4 Hz), 4.55 (1H, dd, J = 14.4, 7.6 Hz) ), 6.93 (1H, d, J = 8.8 Hz), 7.16-7.23 (2H, m), 7.29 (1H, td, J = 7.4, 1.8 Hz), 7 .42-7.50 (3H, m), 8.78 (1H, dd, J = 7.6, 4.4 Hz), 10.85 (1H, s)

Example 36
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-methylbenzamide [6-chloro Example 27 using 2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 4-methylbenzoic acid as raw materials The title compound was obtained by a method according to.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.30 (3H, s), 3.82 (1H, dd, J = 14.6, 4.4 Hz), 4.58 (1H, dd, J = 14.6, 7.8 Hz), 6.90 (1H, d, J = 8.3 Hz), 7.20 (2H, d, J = 8.3 Hz), 7.40-7.48 (2H M), 7.57 (2H, d, J = 8.3 Hz), 8.69 (1H, dd, J = 7.8, 4.4 Hz), 10.84 (1H, s)

Example 37
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -2-methylbenzamide [6-chloro Example 27 Using 2-Oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 2-methylbenzoic acid as raw materials The title compound was obtained by a method according to.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.01 (3H, s), 3.76 (1H, dd, J = 14.6, 4.4 Hz), 4.62 (1H, dd, J = 14.6, 7.8 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.04-7.06 (1H, m), 7.13-7.16 (2H, m ), 7.23-7.29 (1H, m), 7.47-7.50 (2H, m), 8.75 (1H, dd, J = 7.8, 4.4 Hz), 10.85. (1H, s)

Example 38
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -3-methylbenzamide [6-chloro Example 27 using 2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 3-methylbenzoic acid as raw materials The title compound was obtained by a method according to.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.29 (3H, s), 3.83 (1H, dd, J = 14.6, 4.4 Hz), 4.58 (1H, dd, J = 14.6, 7.8 Hz), 6.91 (1H, d, J = 8.3 Hz), 7.25-7.31 (2H, m), 7.41-7.49 (5H, m ), 8.73 (1H, dd, J = 7.8, 4.4 Hz), 10.86 (1H, s)

Example 39
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} biphenyl-4-carboxamide [6- Example using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 4-phenylbenzoic acid as raw materials The title compound was obtained by a method according to No. 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.87 (1H, dd, J = 14.6, 4.4 Hz), 4.62 (1H, dd, J = 14.6, 7.8 Hz) ), 6.92 (1H, d, J = 8.3 Hz), 7.37-7.49 (5H, m), 7.64-7.79 (6H, m), 8.84 (1H, dd) , J = 7.8, 4.4 Hz), 10.86 (1H, s)

Example 40
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} biphenyl-2-carboxamide [6- Example using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 2-phenylbenzoic acid as raw materials The title compound was obtained by a method according to No. 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.70 (1 H, dd, J = 14.4, 4.6 Hz), 4.37 (1 H, dd, J = 14.4, 7.3 Hz) ), 6.95 (1H, d, J = 8.8 Hz), 7.00 (1H, dd, J = 7.6, 1.2 Hz), 7.21-7.25 (2H, m), 7 .27-7.36 (5H, m), 7.41-7.51 (3H, m), 8.65 (1H, dd, J = 7.3, 4.6 Hz), 10.83 (1H, s)

Example 41
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} isonicotinamide [6-chloro-2 -Oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and isonicotinic acid as raw materials and a method according to Example 27 Gave the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.90 (1H, dd, J = 14.6, 4.4 Hz), 4.57 (1H, dd, J = 14.6, 7.6 Hz) ), 6.92 (1H, d, J = 8.5 Hz), 7.43-7.49 (2H, m), 7.53 (2H, dd, J = 4.4, 1.5 Hz), 8 .66 (2H, dd, J = 4.4, 1.5 Hz), 9.08 (1H, dd, J = 7.6, 4.4 Hz), 10.87 (1H, s)

Example 42
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} nicotinamide [6-chloro-2- Using the method according to Example 27 using oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and nicotinic acid as raw materials A compound was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.89 (1H, dd, J = 14.6, 4.4 Hz), 4.58 (1H, dd, J = 14.6, 7.8 Hz) ), 6.92 (1H, d, J = 8.3 Hz), 7.41-7.52 (3H, m), 7.98 (1H, dt, J = 7.8, 2.0 Hz), 8 .66 (1H, dd, J = 4.9, 2.0 Hz), 8.75 (1H, d, J = 2.0 Hz), 8.99 (1H, dd, J = 7.8, 4.4 Hz) ), 10.87 (1H, s)

Example 43
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} pyridine-2-carboxamide [6- Conducted using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and pyridine-2-carboxylic acid as raw materials The title compound was obtained by a method according to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.16 (1H, dd, J = 14.6, 5.9 Hz), 4.42 (1H, dd, J = 14.6, 7.3 Hz) ), 6.91 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 8.8, 2.2 Hz), 7.57-7.62 (1H, m), 7 .63-7.65 (1H, brm), 7.94-8.02 (2H, m), 8.57-8.62 (1H, m), 8.73 (1H, t, J = 6. 6Hz), 10.88 (1H, s)

Example 44
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-methoxybenzamide [6-chloro Example 27 using 2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 4-methoxybenzoic acid as raw materials The title compound was obtained by a method according to.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.76 (3H, s), 3.81 (1H, dd, J = 14.4, 4.4 Hz), 4.57 (1H, dd, J = 14.4, 7.8 Hz), 6.88-6.95 (3H, m), 7.41-7.45 (2H, m), 7.64-7.68 (2H, m), 8.61 (1H, dd, J = 7.8, 4.4 Hz), 10.84 (1H, s)

Example 45
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4- (trifluoromethyl) benzamide [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 4-trifluoromethylbenzoic acid as raw materials And the title compound was obtained by a method according to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.89 (1H, dd, J = 14.6, 4.4 Hz), 4.59 (1H, dd, J = 14.6, 7.8 Hz) ), 6.91 (1H, d, J = 8.5 Hz), 7.45 (1H, dd, J = 8.5, 2.2 Hz), 7.48 (1H, s), 7.78-7. .84 (4H, m), 9.03 (1H, dd, J = 7.8, 4.4 Hz), 10.86 (1H, s)

Example 46
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4- (methanesulfonyl) benzamide [ 6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 4- (methanesulfonyl) benzoic acid as raw materials And the title compound was obtained by a method according to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.22 (3H, s), 3.89 (1H, dd, J = 14.6, 4.0 Hz), 4.60 (1H, dd, J = 14.6, 7.8 Hz), 6.91 (1H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.8, 2.4 Hz), 7.48 (1H , S), 7.86 (2H, dd, J = 6.8, 2.0 Hz), 7.96 (2H, dd, J = 6.8, 2.0 Hz), 9.06 (1H, dd, J = 7.6, 4.0 Hz), 10.87 (1H, s)

Example 47
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -6-fluoronicotinamide [6- Examples using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 6-fluoronicotinic acid as raw materials The title compound was obtained by a method according to No. 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.90 (1H, dd, J = 14.6, 4.1 Hz), 4.58 (1H, dd, J = 14.6, 7.6 Hz) ), 6.92 (1H, d, J = 8.3 Hz), 7.25 (1H, dd, J = 8.3, 2.2 Hz), 7.43-7.49 (2H, m), 8 .20 (1H, td, J = 8.2, 2.9 Hz), 8.48 (1H, d, J = 2.9 Hz), 9.00 (1H, dd, J = 7.6, 4.1 Hz) ), 10.88 (1H, s)

Example 48
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -6-methylnicotinamide [6- Examples using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 6-methylnicotinic acid as raw materials The title compound was obtained by a method according to No. 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.46 (3H, s), 3.86 (1H, dd, J = 14.6, 3.9 Hz), 4.58 (1H, dd, J = 14.6, 7.8 Hz), 6.91 (1H, d, J = 8.8 Hz), 7.29 (1H, d, J = 8.8 Hz), 7.43-7.45 (2H) M), 7.89 (1H, dd, J = 8.0, 2.2 Hz), 8.65 (1H, d, J = 2.2 Hz), 8.90 (1H, dd, J = 7. 8, 3.9Hz), 10.86 (1H, s)

Example 49
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -6- (trifluoromethyl) nicotine Amido [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 6- (trifluoromethyl) nicotine The title compound was obtained by a method according to Example 27 using acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.93 (1H, dd, J = 14.6, 3.7 Hz), 4.59 (1H, dd, J = 14.6, 7.3 Hz) ), 6.91 (1H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.8, 2.2 Hz), 7.48 (1H, s), 7.99 (1H) , D, J = 8.3 Hz), 8.24 (1H, dd, J = 8.3, 2.0 Hz), 8.89 (1H, d, J = 2.0 Hz), 9.17-9. 23 (1H, brs), 10.20 (1H, brs)

Example 50
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1,5-dimethyl-1H- Pyrazole-3-carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1,5 The title compound was obtained by the method according to Example 27 using -dimethyl-1H-pyrazole-3-carboxylic acid as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.21 (3H, s), 3.71 (3H, s), 3.95 (1H, dd, J = 14.6, 5.4 Hz) 4.37 (1H, dd, J = 14.6, 7.3 Hz), 6.39 (1H, d, J = 1.0 Hz), 6.91 (1H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.8, 2.4 Hz), 7.54 (1H, s), 8.02 (1H, dd, J = 7.3, 5.4 Hz), 10.84 (1H, s)

Example 51
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} isoxazole-4-carboxamide [6 -Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and isoxazole-4-carboxylic acid as raw materials The title compound was obtained by a method according to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.95 (1H, dd, J = 14.6, 4.9 Hz), 4.48 (1H, dd, J = 14.6, 7.3 Hz) ), 6.92 (1H, d, J = 8.5 Hz), 7.08 (1H, d, J = 2.0 Hz), 7.47 (1H, dd, J = 8.5, 2.2 Hz) , 7.50 (1H, brs), 8.70 (1H, d, J = 2.0 Hz), 9.28-9.34 (1H, m), 10.88 (1H, s)

Example 52
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -2-methoxybenzamide [6-chloro Example 27 Using 2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 2-methoxybenzoic acid as raw materials The title compound was obtained by a method according to.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.66 (3H, s), 4.04 (1H, dd, J = 14.4, 5.6 Hz), 4.47 (1H, dd, J = 14.4, 6.6 Hz), 6.92-7.00 (2 H, m), 7.05 (1 H, d, J = 7.8 Hz), 7.40-7.45 (1 H, m ), 7.48-7.53 (2H, m), 7.62 (1H, s), 8.34 (1H, dd, J = 6.6, 5.6 Hz), 10.89 (1H, s) )

Example 53
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-isopropylbenzamide [6-chloro Example 27 Using 2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 4-isopropylbenzoic acid as raw materials The title compound was obtained by a method according to.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.16 (6H, d, J = 6.8 Hz), 2.84-2.93 (1H, m), 3.82 (1H, dd, J = 14.6, 4.4 Hz), 4.58 (1H, dd, J = 14.6, 7.8 Hz), 6.90 (1 H, d, J = 8.3 Hz), 7.26 (2H) , D, J = 8.3 Hz), 7.41-7.48 (2H, m), 7.58 (2H, d, J = 8.3 Hz), 8.69 (1H, dd, J = 7. 8, 4.4Hz), 10.84 (1H, s)

Example 54
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -6-oxo-1,6- Dihydro-2-pyridinecarboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 6- The title compound was obtained by the method according to Example 27 using oxo-1,6-dihydropyridine-2-carboxylic acid as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.10 (1H, d, J = 14.6 Hz), 4.49 (1H, d, J = 14.6 Hz), 6.72-6. 79 (1H, brm), 6.95 (1H, d, J = 8.8 Hz), 7.49 (1H, dd, J = 8.8, 2.2 Hz), 7.61 (1H, s), 7.66-7.75 (2H, brm)

Example 55
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1-methyl-1H-pyrazole- 3-Carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1-methyl-1H The title compound was obtained by a method according to Example 27 using -pyrazole-3-carboxylic acid as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.85 (3H, s), 3.98 (1H, d, J = 14.6 Hz), 4.39 (1H, dd, J = 14. 6, 6.6 Hz), 6.61 (1 H, d, J = 2.0 Hz), 6.93 (1 H, d, J = 8.8 Hz), 7.47 (1 H, dd, J = 8.8) 2.2 Hz), 7.56 (1 H, brs), 7.74 (1 H, d, J = 2.0 Hz), 8.15 (1 H, t, J = 6.6 Hz), 10.86 (1 H , Brs)

Example 56
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1H-pyrazole-3-carboxamide [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1H-pyrazole-3-carboxylic acid The title compound was obtained by a method according to Example 27, using as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.98 (1H, d, J = 14.6 Hz), 4.41 (1H, d, J = 14.6 Hz), 6.65 (1H, brs), 6.92 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 8.8, 2.2 Hz), 7.58 (1H, brs), 7.76 ( 1H, brs)

Example 57
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1H-pyrazole-4-carboxamide [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1H-pyrazole-4-carboxylic acid The title compound was obtained by a method according to Example 27, using as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.76 (1H, dd, J = 14.6, 4.4 Hz), 4.59 (1H, dd, J = 14.6, 8.0 Hz) ), 6.92 (1H, dd, J = 8.3, 1.5 Hz), 7.42-7.46 (1H, m), 7.48 (1H, s), 7.84 (1H, brs) ), 8.17 (1H, brs), 8.35 (1H, dd, J = 8.0, 4.4 Hz), 10.87 (1H, s)

Example 58
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} pyridazine-3-carboxamide [6- Conducted using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and pyridazine-3-carboxylic acid as raw materials The title compound was obtained by a method according to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.19 (1H, d, J = 14.6 Hz), 4.44 (1 H, d, J = 14.6 Hz), 6.91 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 8.8, 2.4 Hz), 7.62 (1H, s), 7.90 (1H, dd, J = 8.3) , 5.1 Hz), 8.17 (1H, dd, J = 8.3, 1.7 Hz), 8.32 (1H, brs), 9.40 (1H, dd, J = 5.1, 1.. 7Hz)

Example 59
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} pyrimidine-2-carboxamide [6- Conducted using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and pyrimidine-2-carboxylic acid as raw materials The title compound was obtained by a method according to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.12 (1H, d, J = 14.1 Hz), 4.45 (1H, d, J = 14.1 Hz), 6.92 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 7.63 (1H, s), 7.67 (1H, t, J = 4.9 Hz) ), 8.93 (2H, d, J = 4.9 Hz)

Example 60
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} pyrimidine-4-carboxamide [6- Conducted using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and pyrimidine-4-carboxylic acid as raw materials The title compound was obtained by a method according to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.16 (1H, d, J = 14.6 Hz), 4.41 (1H, d, J = 14.6 Hz), 6.92 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 7.62 (1H, s), 7.97 (1H, dd, J = 5.4) , 1.5 Hz), 9.05 (1 H, d, J = 5.4 Hz), 9.30 (1 H, d, J = 1.5 Hz)

Example 61
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} pyrimidine-5-carboxamide [6- Conducted using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and pyrimidine-5-carboxylic acid as raw materials The title compound was obtained by a method according to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.94 (1H, d, J = 14.6 Hz), 4.58 (1H, d, J = 14.6 Hz), 6.93 (1H, d, J = 8.3 Hz), 7.44-7.52 (2H, m), 8.95 (2H, s), 9.29 (1H, brs), 9.29 (1H, s)

Example 62
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1,3-oxazole-5 Carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1,3-oxazole-5 The title compound was obtained by the method according to Example 27 using carboxylic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.90 (1 H, d, J = 14.1 Hz), 4.49 (1 H, dd, J = 14.1, 6.3 Hz), 6. 91 (1H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.8, 2.2 Hz), 7.50 (1H, s), 7.81 (1H, d, J = 1.0 Hz), 8.53 (1H, s), 8.93-8.99 (1H, brm)

Example 63
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1,3-oxazole-2- Carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1,3-oxazole-2 The title compound was obtained by the method according to Example 27 using carboxylic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.02 (1H, d, J = 14.4 Hz), 4.38 (1 H, dd, J = 14.4, 5.6 Hz), 6. 92 (1H, d, J = 8.5 Hz), 7.43 (1H, brs), 7.47 (1H, dd, J = 8.5, 2.2 Hz), 7.54 (1H, brs), 8.31 (1H, brs), 9.16 (1H, brs)

Example 64
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1,3-oxazole-4- Carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1,3-oxazole-4 The title compound was obtained by the method according to Example 27 using carboxylic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.00 (1H, dd, J = 14.6, 3.4 Hz), 4.39 (1H, dd, J = 14.6, 5.9 Hz) ), 6.92 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 8.8, 2.2 Hz), 7.56 (1H, s), 8.35-8. .38 (1H, m), 8.48 (1H, s), 8.67 (1H, t, J = 1.0 Hz)

Example 65
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} isoxazole-5-carboxamide [6 -Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and isoxazole-5-carboxylic acid as raw materials The title compound was obtained by a method according to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.95 (1H, d, J = 14.6 Hz), 4.48 (1H, d, J = 14.6 Hz), 6.93 (1H, d, J = 8.5 Hz), 7.09 (1H, d, J = 2.0 Hz), 7.47 (1H, dd, J = 8.5, 2.2 Hz), 7.51 (1H, brs) ), 8.71 (1H, d, J = 2.0 Hz), 9.31 (1H, brs)

Example 66
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -2-methylpropionamide [6- Example using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 2-methylpropionic acid as raw materials The title compound was obtained by a method according to No. 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.64 (3H, d, J = 6.8 Hz), 0.88 (3H, d, J = 6.8 Hz), 2.24-2. 32 (1H, m), 3.53 (1H, d, J = 14.6 Hz), 4.44 (1H, dd, J = 14.6, 6.3 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.27 (1 H, brs), 7.46 (1 H, dd, J = 8.8, 2.2 Hz), 8.18-8.23 (1 H, m)

Example 67
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} cyclopropanecarboxamide [6-chloro- 2-Oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and cyclopropanecarboxylic acid were used as raw materials according to Example 27 The title compound was obtained by the method described above.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.46-0.72 (4H, m), 1.50-1.56 (1H, m), 3.66 (1H, d, J = 14.6 Hz), 4.43 (1H, dd, J = 14.6, 5.9 Hz), 6.95 (1H, d, J = 8.8 Hz), 7.37 (1H, d, J = 2) .0Hz), 7.49 (1H, dd, J = 8.8, 2.0 Hz), 8.44-8.49 (1H, m)

Example 68
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -2,2-dimethylpropionamide [ Starting from 6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 2,2-dimethylpropionic acid And the title compound was obtained by a method analogous to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.88 (9 H, s), 3.52 (1 H, d, J = 14.6 Hz), 4.46 (1 H, dd, J = 14. 6, 7.3 Hz), 6.91 (1 H, d, J = 8.8 Hz), 7.23 (1 H, brs), 7.45 (1 H, dd, J = 8.8, 2.2 Hz), 7.83 (1H, m)

Example 69
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -2-ethylbutanamide [6- Conducted using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 2-ethylbutanecarboxylic acid as raw materials The title compound was obtained by a method according to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.37 (3H, t, J = 7.6 Hz), 0.71 (3H, t, J = 7.6 Hz), 1.09-1. 44 (4H, m), 1.89-1.99 (1 H, m), 3.55 (1 H, d, J = 14.6 Hz), 4.52 (1 H, dd, J = 14.6, 6 .3 Hz), 6.92 (1 H, d, J = 8.8 Hz), 7.36 (1 H, brs), 7.45 (1 H, dd, J = 8.8, 2.2 Hz), 8.21 -8.27 (1H, m)

Example 70
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -2-phenylacetamide [6-chloro In accordance with Example 99 using 2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and phenylacetyl chloride as raw materials The title compound was obtained by the method described above.
¹ H-NMR (400 MHz, CD ₃ OD) δ: 3.38 (2H, m), 3.64 (1H, d, J = 14.6 Hz), 4.57 (1H, d, J = 14.6 Hz) ), 6.81 (1H, d, J = 9.3 Hz), 6.95-6.97 (2H, m), 7.11-7.17 (3H, m), 7.28-7.36. (2H, m)

Example 71
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -2- (4-fluorophenyl) Acetamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and (4-fluorophenyl) acetic acid The title compound was obtained by a method according to Example 27, using as a raw material.
¹ H-NMR (400 MHz, CD ₃ OD) δ: 3.22-3.42 (2H, m), 3.63 (1H, d, J = 14.6 Hz), 4.57 (1H, d, J = 14.6Hz), 6.78-6.91 (3H, m), 6.98 (2H, dd, J = 8.8, 5.4Hz), 7.27-7.35 (2H, m)

Example 72
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} isoxazole-3-carboxamide [6 -Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and isoxazole-3-carboxylic acid as raw materials The title compound was obtained by a method according to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.99 (1H, d, J = 14.6 Hz), 4.44 (1 H, dd, J = 14.6, 6.1 Hz), 6. 84-6.86 (1H, m), 6.92 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 7.51 (1H , Brs), 9.06 (1H, d, J = 1.5 Hz), 9.08-9.14 (1H, m)

Example 73
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1,3-thiazole-4- Carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1,3-thiazole-4 The title compound was obtained by the method according to Example 27 using carboxylic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.08 (1 H, d, J = 14.4 Hz), 4.40 (1 H, dd, J = 14.4, 5.6 Hz), 6. 91 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 8.8, 2.4 Hz), 7.60 (1H, s), 8.37 (1H, dd, J = 2.0, 1.0 Hz), 8.40-8.47 (1H, brm), 9.14 (1H, d, J = 2.0 Hz)

Example 74
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -5-ethylisoxazole-3- Carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 5-ethylisoxazole-3 The title compound was obtained by the method according to Example 27 using carboxylic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.20 (3H, t, J = 7.8 Hz), 2.77 (2H, q, J = 7.8 Hz), 3.96 (1H, d, J = 14.6 Hz), 4.42 (1H, dd, J = 14.6, 5.6 Hz), 6.53 (1H, s), 6.92 (1H, d, J = 8.5 Hz) ), 7.46 (1H, dd, J = 8.5, 2.2 Hz), 7.50 (1H, brs), 8.98-9.03 (1H, m)

Example 75
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -2-methyl-1,3- Thiazol-4-carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 2-methyl The title compound was obtained by the method according to Example 27 using -1,3-thiazole-4-carboxylic acid as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.66 (3H, s), 4.06 (1H, d, J = 14.4 Hz), 4.39 (1H, dd, J = 14. 4, 5.6 Hz), 6.92 (1 H, d, J = 8.8 Hz), 7.47 (1 H, dd, J = 8.8, 2.4 Hz), 7.59 (1 H, s), 8.15 (1H, s), 8.30-8.35 (1H, m)

Example 76
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1,3-thiazol-2- Carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1,3-thiazole-2 The title compound was obtained by the method according to Example 27 using carboxylic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.09 (1H, dd, J = 14.8, 3.5 Hz), 4.38 (1H, dd, J = 14.8, 5.8 Hz) ), 6.93 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8, 2.3 Hz), 7.57 (1H, brs), 7.98 (1H) , D, J = 3.1 Hz), 8.05 (1H, d, J = 3.1 Hz), 8.96-9.01 (1H, m)

Example 77
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1,3-thiazole-5 Carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1,3-thiazole-5 The title compound was obtained by the method according to Example 27 using carboxylic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.89 (1H, d, J = 14.6 Hz), 4.54 (1 H, d, J = 14.6 Hz), 6.93 (1H, d, J = 8.6 Hz), 7.44-7.51 (2H, m), 8.42 (1H, s), 9.02-9.08 (1H, m), 9.21 (1H, s)

Example 78
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1,2,5-thiadiazole- 3-Carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1,2,5 -The title compound was obtained by the method according to Example 27 using thiadiazole-3-carboxylic acid as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.06 (1H, d, J = 15.5 Hz), 4.45 (1H, d, J = 15.5 Hz), 6.92 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J = 8.6 Hz), 7.58 (1H, s), 9.11 (1H, brs), 9.16 (1H, s)

Example 79
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -5-methyl-1,3 4-oxadiazol-2-carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride And the title compound was obtained by the method according to Example 27 using 5-methyl-1,3,4-oxadiazole-2-carboxylic acid as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.55 (3H, s), 4.04 (1H, d, J = 14.6 Hz), 4.41 (1H, d, J = 14. 6 Hz), 6.94 (1 H, d, J = 8.8 Hz), 7.49 (1 H, dd, J = 8.8, 2.2 Hz), 7.55 (1 H, brs), 9.61 ( 1H, brs)

Example 80
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1,2,5-oxadi Azol-3-carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1,2, , 5-oxadiazole-3-carboxylic acid was used as a starting material, and the title compound was obtained by the method according to Example 27.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.99 (1H, dd, J = 14.6, 5.9 Hz), 4.31 (1H, dd, J = 14.6, 6.8 Hz) ), 6.93 (1H, dd, J = 8.8, 4.9 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 7.54 (1H, s), 8 .35 (1H, brs), 10.85 (1H, s)

Example 81
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-methyl-1,2, 5-Oxadiazole-3-carboxamide [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride And the title compound was obtained by the method according to Example 27 using 4-methyl-1,2,5-oxadiazole-3-carboxylic acid as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.29 (3H, s), 3.99 (1H, dd, J = 14.6, 4.9 Hz), 4.51 (1H, dd, J = 14.6, 6.8 Hz), 6.94 (1H, d, J = 8.8 Hz), 7.49 (1H, dd, J = 8.8, 2.9 Hz), 7.52 (1H , S), 9.49-9.55 (1H, m), 10.89 (1H, s)

Example 82
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -5-cyclopropylisoxazole-3 -Carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 5-cyclopropylisoxazole The title compound was obtained by a method according to Example 27 using -3-carboxylic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.85-0.91 (2H, m), 1.03-1.08 (2H, m), 2.10-2.19 (1H, m), 3.94 (1H, dd, J = 14.6, 4.9 Hz), 4.40 (1H, dd, J = 14.6, 6.8 Hz), 6.44 (1H, s), 6.91 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 8.8, 2.4 Hz), 7.49 (1H, s), 8.95 (1H, dd) , J = 6.8, 4.9 Hz)

Example 83
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -5-phenylisoxazole-3- Carboxamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 5-phenylisoxazole-3 The title compound was obtained by the method according to Example 27 using carboxylic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.00 (1H, dd, J = 14.6, 5.4 Hz), 4.46 (1H, dd, J = 14.6, 7.3 Hz) ), 6.93 (1H, d, J = 8.5 Hz), 7.33 (1H, s), 7.47 (1H, dd, J = 8.5, 2.2 Hz), 7.50-7 .55 (4H, m), 7.87-7.91 (2H, m), 9.13 (1H, dd, J = 7.3, 5.4 Hz)

Example 84
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (4-fluorophenyl) propanamide 1 ) Synthesis of 6-chloro-4- (3-hydroxypropyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one According to Example 1, known (J .Org.Chem.1998,63,8536) was synthesized using 1- (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone and 3-butenylmagnesium bromide as raw materials. This compound can also be synthesized by the method shown in Reference Example 3.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.17-1.28 (2H, m), 1.38-1.50 (2H, m), 3.40-3.43 (2H, m), 6.97 (1H, d, J = 8.8 Hz), 7.49 (1H, dd, J = 8.8, 2.0 Hz), 7.56 (1H, d, J = 2.0 Hz) ), 10.84 (1H, s).
2) Synthesis of 3- [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propanoic acid 6-Chloro-4- Stir into a solution of (3-hydroxypropyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one (1.0 g, 3.23 mmol) in acetone (20 mL). lower, Jones reagent (8N chromic _acid, H _{2 SO} 4 -H 2 O solution, 2 mL) was added dropwise at room temperature. Water (20 mL) was added, and after stirring at room temperature for 3 hours, 2-propanol was added to the reaction solution, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was diluted with ethyl acetate, 8N aqueous sodium hydroxide solution was added, and the aqueous layer was separated. The aqueous layer was acidified with 8N hydrochloric acid, and the solution was diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain the desired product (726 mg, 70%) as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.07-2.15 (1H, m), 2.22-2.40 (2H, m), 2.75-2.82 (1H, m), 6.97 (1H, d, J = 8.8 Hz), 7.51 (1H, dd, J = 8.8, 2.2 Hz), 7.64 (1H, s), 10.87 ( 1H, s)
3) 3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (4-fluorophenyl) propane Synthesis of Amides 3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propanoic acid (50 mg, 0.15 mmol) And 4-fluoroaniline (21 mg, 0.18 mmol) were dissolved in DMF (1 mL) and pyridine (31 μL, 0.39 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (35 mg, 0 .18 mmol) was added sequentially. The reaction solution was stirred overnight at room temperature, water was added to the reaction solution, the solution was diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by thin layer silica gel column chromatography (ethyl acetate / hexane = 1/1) to obtain the desired product (33.1 mg, 51%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.19-2.53 (3H, m), 2.75-2.87 (1H, m), 6.96 (1H, d, J = 8.3 Hz), 7.08-7.12 (2H, m), 7.45-7.55 (3H, m), 7.61-7.65 (1H, m), 9.94 (1H, s), 10.87 (1H, s)

Example 85
2- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (4-fluorophenyl) acetamide 1- The title compound was obtained by the method according to Example 84 using (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, allylmagnesium bromide and 4-fluoroaniline as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.25 (1H, d, J = 16.1 Hz), 3.85 (1H, d, J = 16.1 Hz), 6.92 (1H, d, J = 8.8 Hz), 7.10 (2H, t, J = 8.8 Hz), 7.42-7.48 (3H, m), 7.67 (1H, brs), 10.25 ( 1H, brs), 10.78 (1H, brs).

Example 86
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N-pyridin-4-ylpropanamide 1 The title compound was obtained by the method according to Example 84 using (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 4-aminopyridine as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.27-2.38 (1H, m), 2.41-2.55 (2H, m), 2.80-2.87 (1H, m), 6.97 (1H, d, J = 8.8 Hz), 7.45-7.52 (3H, m), 7.64 (1H, d, J = 2.0 Hz), 8.39 ( 2H, dd, J = 4.9, 1.5 Hz), 10.28 (1H, s)

Example 87
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N-pyridin-3-ylpropanamide 1 The title compound was obtained by a method according to Example 84 using (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 3-aminopyridine as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.37-2.26 (1H, m), 2.54-2.39 (2H, m), 2.89-2.79 (1H, m), 6.97 (1H, d, J = 8.8 Hz), 7.32 (1H, dd, J = 8.3, 4.9 Hz), 7.48 (1H, dd, J = 8.8). , 2.4 Hz), 7.64 (1H, d, J = 2.4 Hz), 7.94-7.99 (1H, m), 8.23 (1H, dd, J = 4.9, 1.). 5 Hz), 8.64 (1 H, d, J = 2.0 Hz), 10.12 (1 H, s)

Example 88
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (pyridin-2-yl) propanamide The title compound was obtained by the method according to Example 84 using 1- (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 2-aminopyridine as raw materials. It was.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.33-2.56 (3H, m), 2.75-2.92 (1H, m), 6.97 (1H, d, J = 8.5 Hz), 7.05-7.09 (1 H, m), 7.48 (1 H, dd, J = 8.5, 2.2 Hz), 7.62 (1 H, d, J = 2.2 Hz) ), 7.73-7.77 (1H, m), 8.04 (1H, d, J = 8.8 Hz), 8.24-8.29 (1H, m), 10.43 (1H, s) )

Example 89
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (2-methoxyphenyl) propanamide 1 The title compound was obtained by the method according to Example 84 using-(2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 2-methoxyaniline as raw materials. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.31-2.57 (3H, m), 2.73-2.88 (1H, m), 6.85-6.90 (1H, m), 6.94-7.09 (3H, m), 7.49 (1H, dd, J = 8.8, 2.4 Hz), 7.62 (1H, s), 7.86-7. 93 (1H, m), 9.18 (1H, s)

Example 90
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N-isoxazol-3-ylpropanamide 1 The title compound was obtained by the method according to Example 84 using-(2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 3-aminoisoxazole as raw materials. It was.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.33-2.54 (3H, m), 2.78-2.88 (1H, m), 6.88 (1H, d, J = 2.0 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.49 (1H, dd, J = 8.8, 2.4 Hz), 7.61 (1H, d, J = 2) .4 Hz), 8.76 (1 H, d, J = 2.0 Hz), 10.97 (1 H, s)

Example 91
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (6-methoxypyridin-3-yl ) Propanamide 1- (2-Amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 3-amino-6-methoxypyridine were used as raw materials according to Example 84 The title compound was obtained by the method described above.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.19-2.53 (3H, m), 2.77-2.88 (1H, m), 3.80 (3H, s), 6 .77 (1H, d, J = 8.8 Hz), 6.97 (1H, d, J = 8.5 Hz), 7.49 (1H, dd, J = 8.5, 2.2 Hz), 7. 64 (1H, d, J = 2.2 Hz), 7.79-7.83 (1H, m), 8.27 (1H, t, J = 2.2 Hz), 9.92 (1H, s)

Example 92
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (6-fluoropyridin-3-yl ) Propanamide 1- (2-Amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 3-amino-6-fluoropyridine were used as starting materials according to Example 84 The title compound was obtained by the method described above.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 2.26-2.36 (1H, m), 2.38-2.55 (2H, m), 2.80-2.88 (1H, m ), 6.97 (1H, d, J = 8.8 Hz), 7.14 (1H, dd, J = 8.8, 3.4 Hz), 7.48 (1H, dd, J = 8.8, 2.2 Hz), 7.63 (1 H, d, J = 2.2 Hz), 8.04-8.10 (1 H, m), 8.32 (1 H, s), 10.21 (1 H, s)

Example 93
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (6-methylpyridin-3-yl ) Propanamide 1- (2-Amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 3-amino-6-methylpyridine were used as starting materials according to Example 84 The title compound was obtained by the method described above.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.24-2.34 (1H, m), 2.35-2.48 (5H, m), 2.78-2.89 (1H, m), 6.97 (1H, d, J = 8.8 Hz), 7.17 (1H, d, J = 8.3 Hz), 7.49 (1H, dd, J = 8.8, 2.4 Hz) ), 7.64 (1H, d, J = 2.4 Hz), 7.82-7.86 (1H, m), 8.51 (1H, d, J = 2.0 Hz), 10.01 (1H , S)

Example 94
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (3-methoxyphenyl) propanamide 1 The title compound was obtained by the method according to Example 84 using-(2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 3-methoxyaniline as raw materials. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.22-2.30 (1H, m), 2.33-2.53 (2H, m), 2.78-2.86 (1H, m), 3.70 (3H, s), 6.58-6.63 (1H, m), 6.97 (1H, d, J = 8.8 Hz), 7.00-7.05 (1H, m), 7.17 (1H, t, J = 8.0 Hz), 7.24-7.25 (1H, m), 7.49 (1H, dd, J = 8.8, 2.4 Hz), 7.65 (1H, d, J = 2.4 Hz), 9.89 (1H, s)

Example 95
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (3-fluorophenyl) propanamide 1 The title compound was obtained by the method according to Example 84 using-(2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 3-fluoroaniline as raw materials. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.24-2.34 (1H, m), 2.37-2.53 (2H, m), 2.78-2.88 (1H, m), 6.82-6.87 (1H, m), 6.97 (1H, d, J = 8.8 Hz), 7.17-7.21 (1H, m), 7.28-7. 33 (1H, m), 7.48 (1 H, dd, J = 8.8, 2.2 Hz), 7.53 (1 H, m), 7.64 (1 H, d, J = 2.2 Hz), 10.11 (1H, s)

Example 96
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (2-fluorophenyl) propanamide 1 The title compound was obtained by the method according to Example 84 using-(2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 2-fluoroaniline as raw materials. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.36-2.56 (3H, m), 2.78-2.89 (1H, m), 6.98 (1H, d, J = 8.8 Hz), 7.10-7.16 (2H, m), 7.17-7.25 (1 H, m), 7.49 (1 H, dd, J = 8.8, 2.4 Hz), 7.63 (1H, s), 7.83-7.92 (1H, m), 9.72 (1H, s)

Example 97
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- [4- (methanesulfonyl) phenyl] Propanamide 1- (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 4- (methanesulfonyl) aniline as raw materials Gave the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.28-2.36 (1H, m), 2.39-2.55 (2H, m), 2.80-2.90 (1H, m), 3.17 (3H, s), 6.97 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 8.8, 2.4 Hz), 7.56- 7.59 (2H, m), 7.63 (1 H, d, 2.4 Hz), 7.76-7.79 (1 H, m), 8.17 (1 H, brs), 10.30 (1 H, s)

Example 98
3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (5-methyl-1H-pyrazole- 3-yl) propanamide 1- (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and 3-amino-5-methyl-1H-pyrazole as raw materials The title compound was obtained by a method according to Example 84.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.16 (3H, s), 2.20-2.46 (3H, m), 2.73-2.84 (1H, m), 6 .23 (1H, s), 6.97 (1H, d, J = 8.8 Hz), 7.49 (1H, dd, J = 8.8, 2.4 Hz), 7.62 (1H, s) , 10.20 (1H, brs)

Example 99
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzenesulfonamide [6- Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride (60 mg, 0.19 mmol) in THF (1 mL) Were stirred at room temperature, and triethylamine (66 μL, 0.47 mmol) and 4-fluorobenzenesulfonyl chloride (44 mg, 0.23 mmol) were sequentially added. After stirring the reaction solution at room temperature overnight, water was added to the reaction solution, the solution was diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by thin layer silica gel column chromatography (ethyl acetate / hexane = 1/1) to obtain the desired product (58 mg, 70%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.49 (1H, d, J = 14.1 Hz), 3.98-4.09 (1H, m), 6.91 (1H, d, J = 8.8 Hz), 7.38 (2H, m), 7.45-7.51 (2H, m), 7.77-7.81 (2H, m), 8.30 (1H, brs)

Example 100
N- {2- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} -4-fluorobenzenesulfonamide Using 1- (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, allylmagnesium bromide and 4-fluorobenzenesulfonyl chloride as raw materials, the title was prepared by a method according to Example 1 and Example 99. A compound was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.19-2.30 (1H, m), 2.59-2.70 (2H, m), 2.74-2.83 (1H, m), 6.93 (1H, d, J = 9.3 Hz), 7.35-7.44 (2H, m), 7.50-7.46 (2H, m), 7.74-7. 83 (3H, m), 10.83 (1H, s).

Example 101
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-methylbenzenesulfonamide [6 -Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 4-methylbenzenesulfonyl chloride as raw materials, The title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.37 (3H, s), 3.40 (1H, dd, J = 14.4, 5.9 Hz), 3.96 (1H, dd, J = 14.4, 7.3 Hz), 6.90 (1H, d, J = 8.8 Hz), 7.34 (2H, d, J = 8.1 Hz), 7.44 (1H, d, J = 2.4 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 7.63 (2H, d, J = 8.1 Hz), 8.13 (1H, dd, J = 7.3, 5.9 Hz), 10.79 (1 H, s)

Example 102
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-methoxybenzenesulfonamide [6 -Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 4-methoxybenzenesulfonyl chloride as raw materials, The title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.38 (1H, dd, J = 14.0, 5.8 Hz), 3.83 (3H, s), 3.94 (1H, dd, J = 14.0, 7.6 Hz), 6.91 (1H, d, J = 8.4 Hz), 7.05 (2H, d, J = 9.1 Hz), 7.43 (1H, d, J = 2.3 Hz), 7.47 (1H, dd, J = 8.4, 2.3 Hz), 7.68 (2H, d, J = 9.1 Hz), 8.05 (1H, dd, J = 7.6, 5.8 Hz), 10.80 (1H, s).

Example 103
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-cyanobenzenesulfonamide [6 -Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 4-cyanobenzenesulfonyl chloride as raw materials, The title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.59 (1H, dd, J = 14.6, 6.3 Hz), 4.14 (1H, dd, J = 14.6, 6.3 Hz) ), 6.91-6.83 (1H, m), 7.43-7.48 (2H, m), 7.84 (2H, d, J = 8.6 Hz), 8.00 (2H, d) , J = 8.6 Hz), 8.58 (1H, t, J = 6.3 Hz), 10.75 (1H, s).

Example 104
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} naphthalene-2-sulfonamide [6- Conducted using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and naphthalene-2-sulfonyl chloride as raw materials The title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.84 (1H, dd, J = 14.3, 6.1 Hz), 4.39 (1H, dd, J = 14.3, 7.2 Hz) ), 7.22-7.14 (1H, m), 7.72-7.83 (2H, m), 7.96-8.12 (3H, m), 8.33-8.47 (3H) M), 8.66 (1H, dd, J = 7.2, 6.1 Hz), 8.71-8.75 (1H, m), 11.09 (1H, s).

Example 105
4-chloro-N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzooxazin-4-yl] methyl} benzenesulfonamide [6 -Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 4-chlorobenzenesulfonyl chloride as raw materials The title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.50 (1H, dd, J = 14.3, 5.9 Hz), 4.05 (1H, dd, J = 14.3, 5.9 Hz) ), 6.90 (1H, d, J = 8.8 Hz), 7.43-7.50 (2H, m), 7.60 (2H, d, J = 8.8 Hz), 7.73 (2H) , D, J = 8.8 Hz), 8.34 (1H, t, J = 5.9 Hz), 10.80 (1H, s).

Example 106
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} pyridine-3-sulfonamide [6- Conducted using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and pyridine-3-sulfonyl chloride as raw materials The title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.57 (1H, d, J = 14.6 Hz), 4.12 (1H, d, J = 14.6 Hz), 6.91 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 8.8, 2.2 Hz), 7.51 (1H, s), 7.58 (1H, dd, J = 8.8) , 4.9 Hz), 8.11 (1H, d, J = 8.8 Hz), 8.78 (1H, d, J = 4.9 Hz), 8.88 (1H, d, J = 2.2 Hz) , 10.81 (1H, brs)

Example 107
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} pyridine-2-sulfonamide [6- Conducted using chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and pyridine-2-sulfonyl chloride as raw materials The title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.76 (1H, d, J = 14.6 Hz), 4.18 (1H, d, J = 14.6 Hz), 6.90 (1H, d, J = 8.8 Hz), 7.44-7.49 (2H, m), 7.63 (1H, m), 7.84 (1H, d, J = 7.8 Hz), 8.04 ( 1H, t, J = 7.8 Hz), 8.66 (1H, d, J = 3.9 Hz)

Example 108
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -1-methyl-1H-imidazole- 4-sulfonamide [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 1-methyl-1H The title compound was obtained by a method according to Example 99 using -imidazole-4-sulfonyl chloride as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.57 (1H, d, J = 14.1 Hz), 3.69 (3H, s), 3.96 (1H, d, J = 14. 1 Hz), 6.93 (1 H, d, J = 8.5 Hz), 7.37 (1 H, s), 7.48 (1 H, dd, J = 8.5, 2.2 Hz), 7.70 ( 1H, brs), 7.75 (1H, d, J = 1.0 Hz)

Example 109
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -3-fluorobenzenesulfonamide [6 -Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 3-fluorobenzenesulfonyl chloride as raw materials, The title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.53 (1H, d, J = 14.1 Hz), 4.08 (1H, d, J = 14.1 Hz), 6.90 (1H, d, J = 8.8 Hz), 7.43-7.53 (4H, m), 7.54-7.63 (2H, m), 10.74-10.83 (1H, brm)

Example 110
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -2-fluorobenzenesulfonamide [6 -Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 2-fluorobenzenesulfonyl chloride as raw materials, The title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.69 (1H, d, J = 14.1 Hz), 4.08-4.19 (1H, brm), 6.85 (1H, d, J = 8.8 Hz), 7.27-7.35 (2H, m), 7.42-7.47 (2H, m), 7.60-7.72 (2H, m), 10.71 ( 1H, brs)

Example 111
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -3,4-difluorobenzenesulfonamide [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 3,4-difluorobenzenesulfonyl chloride The title compound was obtained by a method according to Example 99, using as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.56 (1H, d, J = 14.6 Hz), 4.04-4.14 (1 H, brm), 6.90 (1 H, d, J = 8.8 Hz), 7.46-7.48 (2H, m), 7.57-7.61 (2H, m), 7.67-7.75 (1H, m), 10.79 ( 1H, brs)

Example 112
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -3,5-difluorobenzenesulfonamide [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 3,5-difluorobenzenesulfonyl chloride The title compound was obtained by a method according to Example 99, using as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.62 (1H, d, J = 14.6 Hz), 4.14 (1H, d, J = 14.6 Hz), 6.89 (1H, d, J = 8.8 Hz), 7.33-7.40 (2H, m), 7.43-7.61 (3H, m), 10.80 (1H, brs)

Example 113
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzenesulfonamide [6-chloro-2 -Oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and benzenesulfonyl chloride as starting materials, a method according to Example 99 Gave the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.44 (1H, d, J = 14.6 Hz), 4.00 (1H, d, J = 14.6 Hz), 6.90 (1H, d, J = 9.3 Hz), 7.45-7.49 (2H, m), 7.51-7.56 (2H, m), 7.58-7.64 (1H, m), 7. 78-7.79 (2H, m)

Example 114
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -3-methylbenzenesulfonamide [6 -Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 3-methylbenzenesulfonyl chloride as raw materials, The title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.35 (3H, s), 3.46 (1H, d, J = 14.1 Hz), 4.00 (1H, d, J = 14. 1 Hz), 6.88 (1H, d, J = 9.3 Hz), 7.38-7.42 (2H, m), 7.43-7.48 (2H, m), 7.49-7. 53 (2H, m)

Example 115
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -3-cyanobenzenesulfonamide [6 -Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 3-cyanobenzenesulfonyl chloride as raw materials, The title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.60 (1H, d, J = 14.1 Hz), 4.13 (1H, d, J = 14.1 Hz), 6.87 (1H, d, J = 8.3 Hz), 7.42-7.50 (2H, m), 7.72 (1H, t, J = 7.8 Hz), 7.97 (1H, d, J = 7.8 Hz) ), 8.02-8.11 (2H, m), 8.50 (1H, brs), 10.76 (1H, s)

Example 116
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -3-methoxybenzenesulfonamide [6 -Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 3-methoxybenzenesulfonyl chloride as raw materials, The title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.45 (1H, d, J = 14.1 Hz), 3.78 (3H, s), 4.01 (1H, d, J = 14. 1 Hz), 6.88 (1 H, d, J = 9.3 Hz), 7.15 (1 H, dd, J = 7.8, 2.0 Hz), 7.23 (1 H, t, J = 2.0 Hz) ), 7.29 (1H, d, J = 7.8 Hz), 7.40-7.49 (3H, m), 8.26 (1H, brs), 10.76 (1H, brs)

Example 117
N- {2- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} benzenesulfonamide 1- (2 -Amino-5-chlorophenyl) -2,2,2-trifluoroethanone, allylmagnesium bromide and benzenesulfonyl chloride were used as starting materials, and the title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.21-2.28 (1H, m), 2.58-2.68 (2H, m), 2.73-2.84 (1H, m), 6.92 (1H, d, J = 8.3 Hz), 7.44-7.50 (2H, m), 7.53-7.59 (2H, m), 7.60-7. 65 (1H, m), 7.70-7.80 (3H, m)

Example 118
N- {3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propyl} benzenesulfonamide 1- (2 -Amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and benzenesulfonyl chloride were used as starting materials, and the title compound was obtained by a method according to Example 99.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.07-1.20 (1H, m), 1.28-1.40 (1H, m), 1.93-2.03 (1H, m), 2.38-2.47 (1H, m), 2.75-2.85 (2H, m), 6.93 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8, 2.2 Hz), 7.51-7.65 (5H, m), 7.70-7.76 (2H, m)

Example 119
N- {3- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propyl} pyridine-2-sulfonamide 1 The title compound was obtained by a method according to Example 99 using-(2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, 3-butenylmagnesium bromide and pyridine-2-sulfonyl chloride as raw materials. Obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.11-1.23 (1H, m), 1.30-1.43 (1H, m), 1.95-2.03 (1H, m), 2.39-2.47 (1H, m), 2.93-3.02 (2H, m), 6.94 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 7.52 (1H, s), 7.60-7.64 (1H, m), 7.88 (2H, d, J = 7.8 Hz), 8.04 (1H, td, J = 7.8, 2.0 Hz), 8.64-8.67 (1H, m)

N- {3-[(4R ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propyl} pyridine- Synthesis of 2-sulfonamide N- {3- [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] propyl} pyridine 2-Sulfonamide was optically resolved by HPLC (Chiral Pack AD-H, n-hexane: 2-propanol = 3: 2), and the fraction eluted in the latter half was concentrated to obtain the desired product.

Example 120
N- {2- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} pyridine-2-sulfonamide 1 The title compound was obtained by a method according to Example 99 using-(2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, allylmagnesium bromide and pyridine-2-sulfonyl chloride as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.24-2.32 (1H, m), 2.61-2.71 (1H, m), 2.82-2.92 (1H, m), 2.95-3.07 (1H, m), 6.93 (1H, d, J = 8.8 Hz), 7.46-7.50 (2H, m), 7.63-7. 66 (1H, m), 7.88 (1H, d, J = 7.8 Hz), 7.95 (1H, brs), 8.05 (1H, td, J = 7.8, 2.0 Hz), 8.68-8.70 (1H, m)

N- {2-[(4R ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} pyridine- 2-sulfonamide N- {2- [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl} pyridine-2 -Sulfonamide was subjected to optical resolution with HPLC (Chiral Pack AD-H, hexane: 2-propanol = 3: 1), and the fraction eluted in the latter half was concentrated to obtain the desired product.

Example 121
2- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N-pyridin-2-ylethanesulfonamide 1 ) Synthesis of 6-chloro-4- (2-hydroxyethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one According to Example 1, 1- ( Synthesis was performed using 2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone and allylmagnesium bromide as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.23 (1H, ddd, J = 14.1, 8.3, 5.9 Hz), 2.68 (1H, ddd, J = 14.1) , 8.3, 5.9 Hz), 3.36-3.43 (1 H, m), 3.43-3.51 (1 H, m), 4.65 (1 H, t, J = 5.4 Hz). 6.95 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 8.8, 2.4 Hz), 7.60 (1H, d, J = 2.4 Hz), 10.80 (1H, s).
2) Synthesis of S- (2- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl) ethanethioate 6-chloro-4- (2-hydroxyethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one (500 mg, 1.69 mmol) in ethyl acetate ( 10 mL) solution, triethylamine (236 μL, 1.69 mmol) and methanesulfonyl chloride (132 μL, 1.69 mmol) were added at room temperature and stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The residue obtained after concentration was directly used in the next reaction. To a DMF solution of the obtained mesyl derivative and cesium carbonate (606 mg, 1.86 mmol), thioacetic acid (144 μL, 2.03 mmol) was added at room temperature and heated at 80 ° C. overnight. The reaction was stopped by adding water, extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The residue obtained after concentration was purified by silica gel column chromatography (ethyl acetate / hexane = 2/1) to obtain the desired product (230 mg, 39%) as a brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.21-2.30 (1H, m), 2.27 (3H, s), 2.60-2.70 (1H, m), 2 .86-2.70 (2H, m), 6.95 (1H, d, J = 8.6 Hz), 7.49 (1H, dd, J = 8.6, 2.3 Hz), 7.62 ( 1H, d, J = 2.3 Hz), 10.86 (1H, s).
3) 2- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N-pyridin-2-ylethanesulfone Synthesis of Amides S- (2- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] ethyl) ethanethioate (100 mg, 0.283 mmol) in acetic acid (2 mL) was added 35% aqueous hydrogen peroxide (245 μL, 2.80 mmol) and heated at 70 ° C. for 1 hour. 10% Pd / C (100 mg) was added, and the mixture was stirred for 1 hour to deactivate excess hydrogen peroxide, and then filtered through Celite. The filtrate was concentrated to obtain 102 mg of the desired product. Subsequently, thionyl chloride (2 mL) was added to the obtained sulfonic acid, and the mixture was heated to reflux for 8 hours. After completion of the reaction, concentration was performed under reduced pressure, and the resulting sulfonyl chloride was used as it was in the next reaction. To a THF solution of excess 2-aminopyridine and triethylamine, a THF-chloroform mixed solution of sulfonyl chloride was added dropwise and stirred at room temperature overnight. After completion of the reaction, water was added, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The residue obtained after concentration was purified by reverse phase HPLC to obtain the desired product (6.6 mg, 9%) as a brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.44-2.57 (3H, m), 2.84-2.96 (1H, m), 6.91-7.09 (3H, m), 6.95 (1H, d, J = 8.7 Hz), 7.44 (1H, d, J = 2.2 Hz), 7.48 (1H, dd, J = 8.7, 2.2 Hz) ), 7.71-7.77 (1H, m), 8.00-8.16 (1H, m), 10.88 (1H, s).

Example 122
2- [6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] -N- (4-fluorophenyl) ethanesulfonamide The title compound was obtained by the method according to Example 121 using 1- (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone, allylmagnesium bromide and 4-fluoroaniline as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.42-2.57 (1H, m), 2.78-2.95 (2H, m), 3.08-3.20 (1H, m), 6.92 (1H, d, J = 8.4 Hz), 7.11-7.27 (4H, m), 7.43 (1H, d, J = 2.2 Hz), 7.47 ( 1H, dd, J = 8.4, 2.2 Hz), 9.92 (1H, s), 10.86 (1H, s).

Example 123
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -N '-(4-fluorophenyl) Synthesis of urea [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride (60 mg, 0.20 mmol) Triethylamine (66 μL, 0.47 mmol) and 4-fluorophenyl isocyanate (32 mg, 0.24 mmol) were sequentially added to a stirred solution of THF (1 mL) at room temperature. After stirring the reaction solution at room temperature overnight, the reaction solution was concentrated. The residue was purified by thin layer silica gel column chromatography (ethyl acetate / hexane = 1/1) to obtain the desired product (24 mg, 28%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.88 (1H, dd, J = 14.6, 5.9 Hz), 4.26 (1H, dd, J = 14.6, 6.8 Hz) ), 6.44 (1H, t, J = 6.3 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.04 (2H, t, J = 8.8 Hz), 7.27 −7.35 (2H, m), 7.49 (1H, dd, J = 8.3, 2.4 Hz), 7.59 (1H, d, J = 2.0 Hz), 8.47 (1H, s), 10.92 (1H, s)

N-{[(4S ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -N'- (4-Fluorophenyl) urea N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -N '-(4-Fluorophenyl) urea was optically resolved by HPLC (Chiral Pack AD-H, n-hexane: 2-propanol = 3: 1), and the fraction eluted in the latter half was concentrated to obtain the target product. Obtained.

Example 124
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -N'-pyridin-4-ylurea Using [6-chloro-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methylamine hydrochloride and 3-isocyanate pyridine as raw materials, The title compound was obtained by a method according to Example 123.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.91 (1H, dd, J = 14.6, 4.4 Hz), 4.28 (1H, dd, J = 14.6, 4.4 Hz) ), 6.62 (1H, t, J = 6.1 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.24 (1H, dd, J = 8.3, 4.9 Hz) 7.49 (1H, dd, J = 8.8, 2.4 Hz), 7.60 (1H, brs), 7.77-7.84 (1H, m), 8.11 (1H, dd, J = 4.9, 2.4 Hz), 8.44 (1 H, d, J = 2.4 Hz), 8.63 (1 H, s), 10.93 (1 H, brs)

Example 125
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide 1) Synthesis of 1- (5-bromo-2-fluorophenyl) -2,2,2-trifluoroethanone A solution of diisopropylamine (56.4 g, 0.55 mol) in THF (500 mL) was −40 Under stirring at 0 ° C., n-butyllithium (200 mL, 2.66 M hexane solution) was added dropwise. After stirring at −40 ° C. for 1 hour, the mixture was cooled to −78 ° C., and a solution of 4-fluorobromobenzene (87.5 g, 0.50 mol) in THF (100 mL) was added. The internal temperature of the reaction solution exceeded −70 ° C. Slowly added dropwise so that there was no. The reaction solution was stirred at −78 ° C. for 1 hour, and then a solution of ethyl trifluoroacetate (65.4 mL, 0.55 mol) in THF (100 mL) was added at the same temperature. The temperature of the reaction solution was raised to 0 ° C. over 1 hour with stirring, a saturated aqueous ammonium chloride solution was added to the reaction solution, the solution was diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4), and the resulting yellow oil was purified again by distillation under reduced pressure (1 mmHg, 53 ° C.) to obtain the desired product (83.8 g, 61. 8%) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.15 (1H, dd, J = 10.2, 8.8 Hz), 7.78 (1H, ddd, J = 8.8, 4.4, 2 .4 Hz), 7.99 (1H, dd, J = 6.3, 2.4 Hz).
2) Synthesis of 1- {5-bromo-2-[(4-methoxybenzyl) amino] phenyl} -2,2,2-trifluoroethanone 1- (5-Bromo-2-fluorophenyl) -2,2 , 2-trifluoroethanone (76.2 g, 0.281 mol), potassium carbonate (46.6 g, 0.337 mol) and 4-methoxybenzylamine (73.4 mL, 0.56 mmol) in toluene (300 mL). did. The reaction solution was stirred overnight with heating under reflux, and then the reaction solution was cooled to 0 ° C., and water (300 mL) and citric acid monohydrate (118 g, 0.56 mol) were sequentially added to the reaction solution at 0 ° C. After stirring the reaction solution at 0 ° C. for 30 minutes, the resulting solid is collected by filtration, the solid is suspended in a mixed solvent of hexane (500 mL) and ethyl acetate (10 mL), and the suspension is stirred at room temperature for 2 hours. did. The solid was collected by filtration, washed with hexane and dried to give the desired product (75.6 g, 69.3%) as an amber solid. The remaining mother liquor was concentrated, and the residue was washed with hexane and a small amount of ethyl acetate to obtain the desired product (15.9 g, 14.5%) as a dark brown solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.81 (3H, s), 4.43 (2H, d, J = 5.4 Hz), 6.69 (1H, d, J = 9.3 Hz) 6.89 (2H, d, J = 8.8 Hz), 7.24 (2H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 9.3, 2.0 Hz), 7.87 (1H, dd, J = 4.4, 2.0 Hz), 9.06 (1H, s).
3) Synthesis of 6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one 1- { Vinylmagnesium in a stirred solution of 5-bromo-2-[(4-methoxybenzyl) amino] phenyl} -2,2,2-trifluoroethanone (75.5 g, 0.195 mol) in THF (500 mL) at 0 ° C. Bromide (1.0 M THF solution, 389 mL) was added dropwise over 1 hour. The reaction solution was stirred at 0 ° C. for 3 hours, saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was further stirred at room temperature for 10 minutes. The reaction solution was diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was dissolved in triethylamine (81.2 mL, 0.59 mol) and toluene (500 mL), and triphosgene (57.9 g, 0.195 mol) was gradually added to the stirred solution at 0 ° C. The reaction solution was stirred at 0 ° C. for 30 minutes, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was further stirred at 0 ° C. for 10 minutes. The reaction solution was diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was suspended in hexane (50 mL) and the suspension was stirred overnight at room temperature. The resulting solid was collected by filtration, washed with hexane and dried to obtain the desired product (71.6 g, 83%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.78 (3H, s), 5.10 (2H, s), 5.69 (1H, d, J = 11.2 Hz), 5.72 (1H , D, J = 17.1 Hz), 6.21 (1H, dd, J = 17.1, 11.2 Hz), 6.80 (1H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 7.40 (1H, dd, J = 8.8, 2.0 Hz), 7.45 (1H, s) ).
4) Synthesis of 6-bromo-4- (hydroxymethyl) -1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one 6-Bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (71.5 g,. 161 mol) was dissolved in dichloromethane (200 mL) and methanol (200 mL), cooled to 0 ° C., and stirred for 2 hours in an ozone stream. After replacing the ozone stream with a nitrogen stream, sodium borohydride (12.2 g, 0.323 mol) was slowly added at 0 ° C. The reaction solution was stirred at 0 ° C. for 10 minutes, and then excess acetone was added. After the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate, and 1N hydrochloric acid was added until the pH of the water bath reached around 6. The organic layer was separated, washed with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was crystallized from water and ethanol to obtain the desired product (62.4 g, 87%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.71 (3H, s), 3.95 (1H, d, J = 12.2 Hz), 4.33 (1H, d, J = 12. 2 Hz), 5.07 (1 H, d, J = 16.6 Hz), 5.14 (1 H, d, J = 16.6 Hz), 5.81 (1 H, brs), 6.90 (2 H, d, J = 8.8 Hz), 7.06 (1H, d, J = 8.8 Hz), 7.20 (2H, d, J = 8.8 Hz), 7.60 (1H, dd, J = 8.8) , 2.0 Hz), 7.74 (1H, d, J = 2.0 Hz).
5) Synthesis of 4- (azidomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one 6 -Bromo-4- (hydroxymethyl) -1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one (61.3 g, 0.137 mol) was dissolved in chloroform (400 mL) and 2,6-dimethylpyridine (48.0 mL, 0.412 mol), and trifluoromethanesulfonic anhydride (46.4 mL, 0.275 mol) was stirred at 0 ° C. Was added dropwise. The reaction solution was stirred for 1 hour under ice cooling, and then a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution under ice cooling. The solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and then dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in DMF (270 mL) and sodium azide (26.7 g, 0.411 mol) was added. The reaction solution was stirred at 80 ° C. for 3 hours and then returned to room temperature, and water was added to the reaction solution. The solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed successively with aqueous citric acid solution, water and saturated brine, and then dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2/3), and the obtained yellow solid was washed with hexane to obtain the desired product (46 g, 71%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.77 (3H, s), 3.90 (1H, d, J = 13.7 Hz), 4.09 (1H, d, J = 13.7 Hz) , 5.07 (1H, d, J = 16.1 Hz), 5.17 (1 H, d, J = 16.1 Hz), 6.84 (1 H, d, J = 8.8 Hz), 6.86 ( 2H, d, J = 8.8 Hz), 7.19 (2H, d, J = 8.8 Hz), 7.33 (1H, s), 7.44 (1H, dd, J = 8.8, 2) .4 Hz).
6) Synthesis of 4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one 4- (azidomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one (46 g, 98. Trimethyl phosphite (23.1 mL, 195 mmol) was added to a mixed solution of THF (130 mL) and water (65 mL) at room temperature, and the reaction solution was stirred at 60 ° C. overnight. The reaction solution was allowed to cool, water was added to the reaction solution, the solution was diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. To the residue was added 4N hydrochloric acid-dioxane solution (200 mL), and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate, washed successively with 2N aqueous sodium hydroxide solution and saturated brine, and the organic layer was dried over magnesium sulfate to give the desired product (30.9 g, 71%). Obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.21 (1H, d, J = 14.1 Hz), 3.61 (1H, d, J = 14.1 Hz), 3.71 (3H, s), 5.05 (1H, d, J = 16.6 Hz), 5.14 (1H, d, J = 16.6 Hz), 6.89 (2H, d, J = 8.8 Hz), 7. 04 (1H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.59 (1H, dd, J = 8.8, 2.4 Hz), 7.69 (1H, d, J = 2.4 Hz).

(4S ^* )-4- (Aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-2- Synthesis of ON 4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one Optical resolution was performed by HPLC (Chiral Pack AD, n-hexane: 2-propanol = 4: 1), and the fraction eluted in the first half was concentrated to obtain the desired product.
7) N-{[6-Bromo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] Synthesis of methyl} -4-fluorobenzamide 4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz Oxazin-2-one (13.67 g, 30.7 mmol), 4-fluorobenzoic acid (4.73 g, 33.8 mmol), hydroxybenzotriazole monohydrate (4.7 g, 30.7 mmol) and triethylamine (4 .69 mL, 33.8 mmol) in DMF (50 mL) with stirring at 0 ° C., 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 6.47 g, 33.8 mmol) was added in small portions. After stirring the reaction solution at room temperature overnight, water was slowly added to the reaction solution. After solid began to precipitate, excess water was further added and stirred at room temperature for 2 hours. The solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the desired product (15.6 g, 90%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.69 (3H, s), 3.91 (1H, dd, J = 14.6, 4.4 Hz), 4.63 (1H, dd, J = 14.6, 7.8 Hz), 5.05 (1H, d, J = 16.6 Hz), 5.13 (1H, d, J = 16.6 Hz), 6.83 (2H, d, J = 8.8 Hz), 7.02 (1H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 7.26 (2H, t, J = 8.8 Hz) 7.56 (1H, dd, J = 8.8, 2.4 Hz), 7.63 (1H, s), 7.75 (2H, dd, J = 8.8, 5.4 Hz), 8. 87 (1H, dd, J = 7.8, 4.4 Hz).
8) Synthesis of N-{[6-bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide N-{[6-Bromo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} An aqueous solution (25 mL) of ceric ammonium nitrate (37.7 g, 68.7 mmol) was added dropwise at room temperature to a solution of -4-fluorobenzamide (13.0 g, 22.9 mmol) in acetonitrile (50 mL) with stirring. The reaction solution was stirred at room temperature for 4 hours. Sodium pyrosulfite was added to the reaction solution, and after stirring for 30 minutes, the solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl acetate-heptane to obtain the desired product (6.7 g: primary crystal, 2.5 g: secondary crystal, 9.2 g, 90% in total) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.85 (1H, d, J = 14.6 Hz), 4.58 (1H, d, J = 14.6 Hz), 6.86 (1H, d, J = 8.8 Hz), 7.26 (2H, t, J = 8.8 Hz), 7.54-7.58 (2H, m), 7.75 (2H, dd, J = 8.8). , 5.4 Hz).
9) 4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-4 Synthesis of -yl] methyl} benzamide N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl}- 4-fluorobenzamide (4.0 g, 8.94 mmol), [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid (2.63 g, 13.42 mmol), chloride Palladium 1,1-bis (diphenylphosphino) ferrocene complex (654 mg, 0.894 mmol) and potassium phosphate trihydrate (4.76 g, 17.88 mmol) were combined with DMF ( 27 mL) and water (2.7 mL), and the mixed solution was stirred at 120 ° C. for 15 minutes under microwave irradiation. After allowing to cool, water (10 mL) and concentrated hydrochloric acid (5 mL) were sequentially added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1), and the foamed solid obtained was recrystallized from ethyl acetate-heptane to obtain the desired product (2.70 g, 69.5%). Was obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.90 (1H, dd, J = 14.6, 3.9 Hz), 4.66 (1H, dd, J = 14.6, 7.3 Hz) ), 6.65 (1H, d, J = 2.0 Hz), 6.95 (1H, d, J = 8.8 Hz), 7.21 (2H, t, J = 8.8 Hz), 7.70. −7.80 (5H, m), 8.82 (1H, dd, J = 7.3, 3.9 Hz), 12.92 (1H, brs).

(4S ^* )-4-fluoro-N-{[2-oxo-6- (1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzo Oxazin-4-yl] methyl} benzamide (4S ^* )-4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H- Example 125 using 3,1-benzoxazin-2-one, 4-fluorobenzoic acid, [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid as raw materials To give the title compound.

Example 126
N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} acetamide 4- (aminomethyl) -6 Example 99 using -bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one and acetyl chloride as starting materials The title compound was obtained by a similar method.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.73 (3H, s), 3.66 (1H, dd, J = 14.6, 4.5 Hz), 4.34 (1H, dd, J = 14.6, 7.0 Hz), 6.88 (1H, d, J = 8.8 Hz), 7.51 (1H, brs), 7.60 (1H, dd, J = 8.8, 2) .4 Hz), 8.22 (1H, dd, J = 7.0, 4.5 Hz).

Example 127
4-fluoro-N-{[2-oxo-6-phenyl-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide N-{[ 6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide and phenylboronic acid as raw materials The title compound was obtained by a method according to Example 125.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.81 (1H, d, J = 14.6 Hz), 4.85 (1H, dd, J = 14.6, 6.8 Hz), 6. 99 (1H, d, J = 8.8 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.35 (1H, t, J = 7.6 Hz), 7.46 (2H, t , J = 7.6 Hz), 7.64-7.68 (4H, m), 7.75 (2H, dd, J = 8.8, 5.4 Hz), 8.89-8.90 (1H, m).

Example 128
3- [4-{[(4-Fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-6-yl] benzoate Acids N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide and 3- The title compound was obtained by the method according to Example 125 using (dihydroxyboryl) benzoic acid as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.84 (1H, dd, J = 14.6, 3.4 Hz), 4.85 (1H, dd, J = 14.6, 8.3 Hz) ), 7.01 (1H, d, J = 8.8 Hz), 7.21 (2H, t, J = 8.8 Hz), 7.59 (1H, t, J = 7.8 Hz), 7.69 −7.72 (2H, m), 7.80 (2H, dd, J = 8.8, 5.4 Hz), 7.90 (2H, dd, J = 17.1, 7.8 Hz), 8. 18 (1H, s), 8.90 (1H, dd, J = 8.3, 3.4 Hz), 10.86 (1H, s).

Example 129
N-{[7-bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide Known Compound 1 Using-(4-bromo-2-fluorophenyl) -2,2,2-trifluoroethanone (Tetrahedron Lett. 2003, 44, 7147) and 4-fluorobenzoic acid as raw materials, the title was prepared by a method according to Example 125. A compound was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.82 (1 H, dd, J = 14.1, 3.9 Hz), 4.56 (1 H, dd, J = 14.1, 7.8 Hz) ), 7.06 (1H, d, J = 2.0 Hz), 7.23-7.25 (3H, m), 7.32 (1H, d, J = 8.8 Hz), 7.74 (2H) , Dd, J = 8.8, 5.4 Hz), 8.77 (1H, dd, J = 7.8, 3.9 Hz).

Example 130
4-fluoro-N-{[6- (2-methylphenyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} Benzamide N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide and (2 The title compound was obtained by a method according to Example 125 using -methylphenyl) boronic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.07 (3H, s), 3.78 (1H, dd, J = 14.6, 3.0 Hz), 4.71 (1H, dd, J = 14.6, 7.8 Hz), 6.97 (1H, d, J = 8.3 Hz), 7.11 (1H, d, J = 7.3 Hz), 7.21-7.27 (6H M), 7.33 (1H, dd, J = 8.3, 2.0 Hz), 7.73 (2H, dd, J = 8.8, 5.4 Hz), 8.84 (1H, dd, J = 7.8, 3.0 Hz).

Example 131
4-Fluoro-N-{[6-isoxazol-4-yl-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl } Benzamide N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide and 4 The title compound was obtained by a method according to Example 125 using-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoxazole as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.95 (1H, d, J = 14.5 Hz), 4.59 (1H, d, J = 14.5 Hz), 6.92 (1H, d, J = 8.2 Hz), 7.19 (2H, t, J = 8.9 Hz), 7.64-7.71 (3H, m), 7.74 (1H, brs), 9.04 ( 1H, brs), 9.32 (1H, brs).

Example 132
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-4-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide The title compound was obtained by a method according to Example 125 using 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.87 (1H, dd, J = 14.1, 3.9 Hz), 4.72 (1H, dd, J = 14.1, 8.3 Hz) ), 6.89 (1H, dd, J = 8.3, 1.5 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.57 (1H, dd, J = 8.3, 1.5 Hz), 7.61 (1H, brs), 7.72 (2H, dd, J = 8.8, 5.4 Hz), 7.96 (2H, brs), 8.83 (1H, dd, J = 8.3, 3.9 Hz), 10.68 (1H, s).

(4S ^* )-4-fluoro-N-{[2-oxo-6- (1H-pyrazol-4-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz Synthesis of Oxazin-4-yl] methyl} benzamide (4S ^* )-4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro- 2H-3,1-benzoxazin-2-one, 4-fluorobenzoic acid, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole The title compound was obtained by a method according to Example 125, using as a raw material.

Example 133
4-Fluoro-N-{[6- (1-methyl-1H-pyrazol-4-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide N-{[6-bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl}- According to Example 125, using 4-fluorobenzamide and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole as raw materials The title compound was obtained by the method.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.85 (3H, s), 3.88 (1H, d, J = 14.6 Hz), 4.70 (1H, dd, J = 14. 6, 7.0 Hz), 6.89 (1H, d, J = 8.3 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.53 (1H, dd, J = 8.3) 2.0 Hz), 7.57 (1H, brs), 7.73 (2H, dd, J = 8.8, 5.4 Hz), 7.77 (1H, s), 8.03 (1H, s) ), 8.85-8.81 (1H, m), 10.70 (1H, brs).
(4S ^* )-4-fluoro-N-{[6- (1-methyl-1H-pyrazol-4-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3 , 1-Benzoxazin-4-yl] methyl} benzamide (4S ^* )-4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1, 4-dihydro-2H-3,1-benzoxazin-2-one, 4-fluorobenzoic acid, 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Il) -1H-pyrazole was used as a raw material, and the title compound was obtained by a method according to Example 125.

Example 134
3- [4-{[(4-Fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] pyridinium Trifluoroacetate N-{[6-bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide and The title compound was obtained by a method according to Example 125 using 3-pyridinylboronic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.87 (1H, dd, J = 14.6, 3.9 Hz), 4.85 (1H, dd, J = 14.6, 8.3 Hz) ), 7.05 (1H, dd, J = 8.3, 1.5 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.72-7.77 (3H, m), 7 .80 (1H, dd, J = 8.3, 1.5 Hz), 7.83 (1H, s), 8.33 (1H, d, J = 7.8 Hz), 8.68 (1H, dd, J = 4.9, 1.5 Hz), 8.92 (1H, dd, J = 8.3, 3.9 Hz), 8.99 (1H, d, J = 2.0 Hz), 10.93 (1H , S).

Example 135
4-Fluoro-N-{[2-oxo-6- (3-thienyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide and 3-thienyl The title compound was obtained by the method according to Example 125 using boronic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.84 (1 H, d, J = 14.6 Hz), 4.80 (1 H, dd, J = 14.6, 6.8 Hz), 6. 94 (1H, d, J = 8.8 Hz), 7.21 (2H, t, J = 9.3 Hz), 7.51 (1H, dd, J = 4.9, 1.5 Hz), 7.65 (1H, dd, J = 4.9, 2.9 Hz), 7.68-7.71 (2H, m), 7.73 (2H, dd, J = 8.8, 5.9 Hz), 7. 77 (1H, dd, J = 2.9, 1.5 Hz), 8.89-8.86 (1H, m).

Example 136
4-Fluoro-N-{[6- (6-methoxypyridin-3-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-4- Yl] methyl} benzamide N-{[6-bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluoro The title compound was obtained by a method according to Example 125 using benzamide and (6-methoxypyridin-3-yl) boronic acid as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.83 (1H, d, J = 14.6 Hz), 3.89 (3H, s), 4.84 (1H, dd, J = 14. 6, 6.8 Hz), 6.93 (1 H, d, J = 8.8 Hz), 6.99 (1 H, d, J = 8.8 Hz), 7.22 (2 H, t, J = 8.8 Hz) ), 7.65-7.67 (2H, m), 7.73 (2H, dd, J = 8.8, 5.4 Hz), 7.99 (1H, dd, J = 8.8, 2. 4 Hz), 8.46 (1 H, d, J = 2.4 Hz), 8.91-8.88 (1 H, m), 10.79-10.83 (1 H, brm).

Example 137
4- [4-{[(4-Fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-6-yl] benzoate Acids N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide and 4- The title compound was obtained by the method according to Example 125 using (dihydroxyboryl) benzoic acid as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.85 (1H, dd, J = 14.4, 3.9 Hz), 4.85 (1H, dd, J = 14.4, 8.3 Hz) ), 7.02 (1H, dd, J = 8.8, 1.0 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.74-7.80 (6H, m), 8 .01 (2H, d, J = 8.3 Hz), 8.91 (1H, dd, J = 8.3, 3.9 Hz), 10.89 (1H, s).

Example 136
4-Fluoro-N-{[6-methyl-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide N-{[ 6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide and trimethylboroxan as raw materials The title compound was obtained by a method according to Example 125.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.21 (3H, s), 3.86 (1H, dd, J = 14.6, 4.4 Hz), 4.54 (1H, dd, J = 14.6, 7.8 Hz), 6.80 (1H, d, J = 7.8 Hz), 7.17 (1H, d, J = 8.3 Hz), 7.21 (1H, s), 7.24 (2H, t, J = 8.8 Hz), 7.73 (2H, dd, J = 8.8, 5.4 Hz), 8.75 (1H, dd, J = 7.8, 4. 4 Hz), 10.58 (1 H, brs).

Example 139
4-Fluoro-N-{[2-oxo-7- (1H-pyrazol-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide N-{[7-bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide The title compound was obtained by a method according to Example 125 using [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid as a raw material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.84 (1H, dd, J = 14.6, 3.9 Hz), 4.63 (1H, dd, J = 14.6, 7.8 Hz) ), 6.67 (1H, d, J = 2.4 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.39 (2H, d, J = 8.3 Hz), 7.46. (1H, dd, J = 8.3, 1.5 Hz), 7.73-7.77 (3H, m), 8.80 (1H, dd, J = 7.8, 3.9 Hz), 10. 75 (1H, s).

Example 140
4-Fluoro-N-{[2-oxo-7- (1H-pyrazol-4-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide N-{[7-bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide The title compound was obtained by a method according to Example 125 using 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.82 (1H, dd, J = 14.6, 3.9 Hz), 4.62 (1H, dd, J = 14.6, 7.8 Hz) ), 7.04 (1H, d, J = 1.5 Hz), 7.23 (2H, t, J = 8.8 Hz), 7.30 (1H, dd, J = 8.3, 1.5 Hz) , 7.34 (1H, d, J = 8.3 Hz), 7.76 (2H, dd, J = 8.8, 5.4 Hz), 7.99 (2H, brs), 8.79 (1H, dd, J = 7.8, 3.9 Hz), 10.68 (1H, s).

Example 141
4-Fluoro-N-{[6- (1-methyl-1H-pyrazol-5-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide N-{[6-bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl}- The title compound was obtained by a method according to Example 125 using 4-fluorobenzamide and (1-methyl-1H-pyrazol-5-yl) boronic acid as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.75 (3H, d, J = 11.7 Hz), 3.82 (1H, dd, J = 14.6, 3.9 Hz), 4. 75 (1H, dd, J = 14.6, 7.8 Hz), 6.37 (1H, d, J = 2.0 Hz), 7.01 (1H, d, J = 8.3 Hz), 7.24 (2H, t, J = 8.8 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.51 (1H, brs), 7.54 (1H, dd, J = 8.3) 2.0 Hz), 7.73 (2H, dd, J = 8.8, 5.4 Hz), 8.86 (1H, dd, J = 7.8, 3.9 Hz).

Example 142
4-Fluoro-N-{[6- (3-methyl-1H-pyrazol-5-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide N-{[6-bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl}- Using 4-fluorobenzamide and [3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid as raw materials, the title compound was prepared by a method according to Example 125. Obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.23 (3H, s), 3.89 (1H, dd, J = 14.6, 3.9 Hz), 4.63 (1H, dd, J = 14.6, 7.8 Hz), 6.37 (1 H, s), 6.91 (1 H, d, J = 8.8 Hz), 7.20 (2 H, t, J = 8.8 Hz), 7.68-7.74 (4H, m), 8.79 (1H, dd, J = 7.8, 3.9 Hz), 10.73 (1H, s).

Example 143
4-Fluoro-N-{[6- (4-methyl-1H-pyrazol-5-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide N-{[6-bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl}- Using 4-fluorobenzamide and [4-Methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid as raw materials, the title compound was prepared by a method according to Example 125. Obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.13 (3H, s), 3.87-3.89 (1H, m), 4.56-4.58 (1H, m), 6 .96 (1H, d, J = 7.8 Hz), 7.21 (2H, t, J = 8.8 Hz), 7.53-7.61 (2H, brm), 7.69 (2H, dd, J = 8.8, 5.4 Hz), 8.78 (1H, dd, J = 7.8, 3.9 Hz), 10.74 (1 H, brs), 12.60 (1 H, s).

Example 144
4-Fluoro-N-{[2-oxo-6- (1H-pyrrol-2-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide The title compound was obtained by a method according to Example 125 using 1- (t-butoxycarbonyl) pyrrole-2-boronic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.98 (1H, dd, J = 14.6, 4.9 Hz), 4.56 (1H, dd, J = 14.6, 7.3 Hz) ), 6.08 (1H, dd, J = 5.9, 2.4 Hz), 6.43-6.46 (1H, brm), 6.82 (1H, d, J = 1.5 Hz), 6 .86 (1H, d, J = 8.3 Hz), 7.21 (2H, t, J = 8.8 Hz), 7.58 (1H, dd, J = 8.3, 2.0 Hz), 7. 66 (1H, s), 7.73 (2H, dd, J = 8.8, 5.9 Hz), 8.76 (1H, dd, J = 7.3, 4.9 Hz), 10.65 (1H , S), 11.21 (1H, s).

Example 145
4-Fluoro-N-{[2-oxo-6- (3-phenyl-1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide N-{[6-bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl}- Using 4-fluorobenzamide and [3-Phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid as raw materials, the title compound was prepared by a method according to Example 125. Obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.98 (1H, dd, J = 14.6, 4.4 Hz), 4.62 (1H, dd, J = 14.6, 7.3 Hz) ), 6.97 (1H, d, J = 8.3 Hz), 7.10 (1H, s), 7.20 (2H, t, J = 8.8 Hz), 7.34 (1H, t, J = 7.3 Hz), 7.46 (2H, t, J = 7.3 Hz), 7.72 (2H, dd, J = 8.8, 5.4 Hz), 7.78-7.83 (3H, m), 7.87 (1H, s), 8.81 (1H, dd, J = 7.3, 4.4 Hz), 10.80 (1H, s).

Example 146
4-Fluoro-N-{[6- (2-furyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide and 2-furylboron The title compound was obtained by a method according to Example 125 using an acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.89 (1H, dd, J = 14.6, 3.9 Hz), 4.67 (1H, dd, J = 14.6, 7.8 Hz) ), 6.59 (1H, dd, J = 3.4, 1.5 Hz), 6.85 (1H, d, J = 3.4 Hz), 6.95 (1H, d, J = 8.3 Hz) , 7.22 (2H, t, J = 8.8 Hz), 7.68-7.74 (5H, m), 8.83 (1H, dd, J = 7.8, 3.9 Hz), 10. 83 (1H, s).

Example 147
4-Fluoro-N-{[2-oxo-6- (2-thienyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide and 2-thienyl The title compound was obtained by the method according to Example 125 using boronic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.83 (1H, dd, J = 14.6, 3.9 Hz), 4.79 (1H, dd, J = 14.6, 8.3 Hz) ), 6.95 (1H, d, J = 8.3 Hz), 7.13 (1H, dd, J = 4.9, 3.9 Hz), 7.22 (2H, t, J = 8.8 Hz) , 7.44 (1H, dd, J = 3.9, 1.0 Hz), 7.53 (1H, dd, J = 4.9, 1.0 Hz), 7.63 (1H, dd, J = 8) .3, 2.0 Hz), 7.66 (1H, brs), 7.74 (2H, dd, J = 8.8, 5.4 Hz), 8.87 (1H, dd, J = 8.3) 3.9 Hz), 10.84 (1 H, s).

Example 148
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-4-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3, 1-benzoxazine-4 -Yl] methyl} benzenesulfonamide 4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine 2-one, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole and (4-fluorophenyl) sulfonyl chloride were used as raw materials. The title compound was obtained by a method analogous to Example 99 and Example 125.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.52 (1H, dd, J = 14.1, 6.0 Hz), 4.09 (1H, dd, J = 14.1, 7.0 Hz) ), 6.87 (1H, d, J = 8.3 Hz), 7.39-7.29 (2H, m), 7.56 (1H, brs), 7.61 (1H, dd, J = 8) .3, 2.0 Hz), 7.84-7.76 (2H, m), 8.01 (2H, s), 8.28 (1H, dd, J = 7.0, 6.0 Hz), 10 .59 (1H, s).

Example 149
N-{[2-oxo-6- (1H-pyrazol-4-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl } Pyridine-2-sulfonamide 4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine- Using 2-one, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole and pyridine-2-sulfonyl chloride as starting materials, Example 99 and The title compound was obtained by a method according to Example 125.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.13 (1H, dd, J = 14.3, 5.4 Hz), 4.58 (1H, dd, J = 14.3, 7.5 Hz) ), 7.16-7.22 (1H, m), 7.86-7.98 (3H, m), 8.13-8.19 (1H, m), 8.29-8.38 (3H) M), 8.77 (1H, dd, J = 7.5, 5.4 Hz), 8.99-8.95 (1H, m), 10.89 (1H, s).

Example 150
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzenesulfonamide 4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-2 According to Example 99 and Example 125, using -one, [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid and 4-fluorobenzenesulfonyl chloride as raw materials The title compound was obtained by the method.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.45-3.55 (1H, m), 3.99-4.06 (1H, m), 6.69 (1H, s), 6 .92 (1H, d, J = 8.8 Hz), 7.30-7.35 (2H, m), 7.69-7.89 (5H, m), 8.28-8.31 (1H, m), 10.69 (1H, s), 12.86 (1H, s)
4-Fluoro-N-{[(4S ^* )-2-oxo-6- (1H-pyrazol-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz Oxazin-4-yl] methyl} benzenesulfonamide (4S ^* )-4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro- 2H-3,1-benzoxazin-2-one, [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid and 4-fluorobenzenesulfonyl chloride as raw materials, The title compound was obtained according to Example 99 and Example 125.

Example 151
N-{[2-oxo-6- (1H-pyrazol-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} pyridine -2-sulfonamide 4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-2- On, [1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid and pyridine-2-sulfonyl chloride as starting materials, a method according to Example 99 and Example 125 Gave the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.81 (1H, d, J = 14.4 Hz), 4.19 (1 H, dd, J = 14.4, 6.6 Hz), 6. 68 (1H, s), 6.92 (1H, d, J = 8.3 Hz), 7.61 (1H, dd, J = 7.8, 4.6 Hz), 7.68-7.89 (4H M), 8.00 (1H, td, J = 7.8, 1.5 Hz), 8.46 (1H, s), 8.65 (1H, s), 10.67 (1H, s), 12.86 (1H, s)
N-{[(4S ^* )-2-oxo-6- (1H-pyrazol-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-4- Yl] methyl} pyridine-2-sulfonamide (4S ^* )-4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro-2H -3,1-benzoxazin-2-one, [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid and pyridine-2-sulfonyl chloride as starting materials The title compound was obtained by a method analogous to Example 99 and Example 125.

Example 152
4-Fluoro-N-{[2-oxo-6- (pyridin-4-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl } Benzamide N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide and 4 -The title compound was obtained by the method according to Example 125 using pyridinylboronic acid as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.85 (1H, dd, J = 14.6, 3.4 Hz), 4.86 (1H, dd, J = 14.6, 7.8 Hz) ), 7.03 (1H, d, J = 8.8 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.69 (2H, d, J = 6.3 Hz), 7.74 (2H, dd, J = 8.8, 5.4 Hz), 7.82-7.84 (2H, m), 8.64 (2H, d, J = 6.3 Hz), 8.91 (1H, dd, J = 7.8, 3.4 Hz), 10.94 (1H, s).

Example 153
4-Fluoro-N-({2-oxo-4- (trifluoromethyl) 6- [3- (trifluoromethyl) -1H-pyrazol-5-yl] -1,4-dihydro-2H-3,1 -Benzoxazin-4-yl} methyl) benzamide N-{[6-bromo-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] According to Example 125 using methyl} -4-fluorobenzamide and [3-trifluoromethyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid as raw materials The title compound was obtained by the method.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.04 (1H, dd, J = 14.6, 4.9 Hz), 4.57 (1H, dd, J = 14.6, 7.3 Hz) ), 7.00 (1H, d, J = 8.8 Hz), 7.15 (1H, s), 7.23 (2H, t, J = 8.8 Hz), 7.72 (2H, dd, J = 8.8, 5.4 Hz), 7.83 (1H, dd, J = 8.8, 2.0 Hz), 7.94 (1H, s), 8.80 (1H, dd, J = 7. 3, 4.9 Hz), 10.93 (1 H, s), 14.08 (1 H, s).

Example 154
4-Fluoro-N-{[2-oxo-6- (2-oxopyrrolidin-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-4- Yl] methyl} benzamide 1) 4-fluoro-N-{[1- (4-methoxybenzyl) -2-oxo-6- (2-oxopyrrolidin-1-yl) -4- (trifluoromethyl) -1 , 4-Dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide N-{[6-Bromo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) ) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide (100 mg, 0.176 mmol), tris (dibenzylideneacetone) diparadiou (8.0 mg, 0.008 mmol), xanthophos (15.2 mg, 0.024 mmol), cesium carbonate (57.4 mg, 0.176 mmol) and 2-pyrrolidinone (26.8 μL, 0.352 mmol) in dioxane (0 .5 mL) The mixed solution was stirred at 120 ° C. for 30 minutes under microwave irradiation. After cooling, the solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to obtain the desired product (69 mg, 69%) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.09-2.20 (2H, m), 2.55 to 2.59 (2H, m), 3.76 (3H, s), 3.78 -3.96 (3H, m), 4.93 (1H, dd, J = 14.6, 8.8 Hz), 5.00 (1H, d, J = 16.1 Hz), 5.14 (1H, d, J = 16.1 Hz), 6.80 (2H, d, J = 8.8 Hz), 6.89 (1H, d, J = 9.3 Hz), 7.02 (2H, t, J = 8) .8 Hz), 7.16 (2H, d, J = 8.8 Hz), 7.35 (1H, d, J = 2.0 Hz), 7.66 (2H, dd, J = 8.8, 4.). 9 Hz), 8.01 (1H, s), 8.05 (1 H, dd, J = 9.3, 2.4 Hz).
2) 4-Fluoro-N-{[2-oxo-6- (2-oxopyrrolidin-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine- Synthesis of 4-yl] methyl} benzamide 4-fluoro-N-{[1- (4-methoxybenzyl) -2-oxo-6- (2-oxopyrrolidin-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide (30 mg, 0.0525 mmol), aluminum trichloride (70 mg, 0.525 mmol) mixed in anisole (0.5 mL) And stirred at room temperature. After completely dissolving, the mixture was heated to 100 ° C. and stirred for 4 hours. After returning to room temperature, the solution was diluted with ethyl acetate, water was added, and then the organic layer was separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/0), and the crude product was crystallized from ethyl acetate-diisopropyl ether to obtain the desired product (10.1 mg, 43%) as a pale yellow solid. It was.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.99-2.07 (2H, m), 2.44-2.48 (2H, m), 3.69-3.81 (2H, m), 3.85 (1H, dd, J = 14.6, 4.4 Hz), 4.56 (1H, dd, J = 14.6, 7.8 Hz), 6.89 (1H, d, J = 8.8 Hz), 7.23 (2H, t, J = 8.8 Hz), 7.50 (1H, d, J = 2.0 Hz), 7.74 (2H, dd, J = 8.8, 5.9 Hz), 7.79 (1 H, dd, J = 8.8, 2.4 Hz), 8.78 (1 H, dd, J = 7.8, 4.4 Hz), 10.67 (1 H, s ).
(4S ^* )-4-fluoro-N-{[2-oxo-6- (2-oxopyrrolidin-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1- Synthesis of benzoxazin-4-yl] methyl} benzamide (4S ^* )-4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -1,4-dihydro The title compound was obtained in the same manner as described above using -2H-3,1-benzoxazin-2-one, 4-fluorobenzoic acid and 2-pyrrolidinone as raw materials.

Example 155
4-Fluoro-N-{[2-oxo-6- (2-oxoazetidin-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide 4-fluoro-N-{[1- (4-methoxybenzyl) -2-oxo-6- (2-oxopyrrolidin-1-yl) -4- (trifluoromethyl) -1,4- The title compound was obtained by the method according to Example 154 using dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide and 2-azetidinone as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.04-3.06 (2H, m), 3.53-3.62 (2H, m), 3.86 (1H, dd, J = 14.6, 4.4 Hz), 4.52 (1H, dd, J = 14.6, 7.8 Hz), 6.89 (1H, d, J = 8.8 Hz), 7.21-7.27 (3H, m), 7.47 (1H, dd, J = 8.8, 2.0 Hz), 7.74 (2H, dd, J = 8.8, 5.9 Hz), 8.78 (1H, brs).

Example 156
4-fluoro-N-{[2-oxo-6- (propionylamino) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide 4 -Fluoro-N-{[1- (4-methoxybenzyl) -2-oxo-6- (2-oxopyrrolidin-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3 , 1-Benzoxazin-4-yl] methyl} benzamide and propionamide as starting materials, the title compound was obtained by the method according to Example 154.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.04 (3H, t, J = 7.3 Hz), 2.27 (2H, q, J = 7.3 Hz), 3.93 (1H, dd, J = 14.1, 4.9 Hz), 4.31 (1H, dd, J = 14.1, 7.3 Hz), 6.82 (1H, d, J = 8.8 Hz), 7.23 (2H, t, J = 8.8 Hz), 7.61-7.65 (2H, m), 7.73 (2H, dd, J = 8.8, 5.9 Hz), 8.74 (1H, dd, J = 7.3, 4.9 Hz), 9.90 (1H, s), 10.58 (1H, s).

Example 157
4-fluoro-N-{[2-oxo-6- (1H-1,2,4-triazol-5-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1- Benzoxazin-4-yl] methyl} benzamide To a solution of 1-[(benzyloxy) methyl] -1H-1,2,4-triazole (41.7 mg, 0.22 mmol) in THF (0.3 mL) was added -78. N-Butyllithium (92 μL, 2.4 M hexane solution) was added dropwise with stirring and cooling at ° C. The reaction solution was stirred at the same temperature for 10 minutes, and then a solution of zinc bromide (59.5 mg, 0.26 mmol) in THF (0.3 mL) was added at -78 ° C. The solution was stirred at −78 ° C. for 20 minutes and then gradually warmed to room temperature. To the reaction solution, tetrakis (triphenylphosphine) palladium (10 mg, 0.009 mmol), N-{[6-bromo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1, 4-Dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide (50 mg, 0.088 mmol) and DMF (0.5 mL) were added, and the mixture was stirred at 100 ° C. overnight. After returning to room temperature, the solution was diluted with ethyl acetate, water was added, and then the organic layer was separated. The organic layer was washed successively with aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by thin layer silica gel chromatography (ethyl acetate / hexane = 2/1) to obtain 36.6 mg of a pale yellow liquid as a crude product.
The obtained crude product (35 mg) was deprotected under the same conditions as in Example 154 to obtain the desired product (5.2 mg, 23%) as a pale white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.95 (1H, dd, J = 14.4, 4.4 Hz), 4.52 (1H, dd, J = 14.4, 7.3 Hz) ), 7.00 (1H, d, J = 8.3 Hz), 7.20 (2H, t, J = 8.8 Hz), 7.69 (2H, dd, J = 8.8, 5.4 Hz) , 7.99 (1H, dd, J = 8.3, 2.0 Hz), 8.05 (1H, brs), 8.42 (1H, brs), 8.79 (1H, dd, J = 7. 3, 4.4 Hz).

Example 158
4-Fluoro-N-{[6- (1H-imidazol-2-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide N-{[6-Bromo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-4- [Il] methyl} -4-fluorobenzamide and imidazole as starting materials, and the title compound was obtained by the method according to Example 154.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.08 (1H, dd, J = 14.1, 4.9 Hz), 4.42 (1H, dd, J = 14.1, 6.3 Hz) ), 6.96 (2H, d, J = 8.8 Hz), 7.21 (3H, t, J = 8.8 Hz), 7.23 (1H, brs), 7.71 (2H, dd, J = 8.8, 5.4 Hz), 7.92 (1H, dd, J = 8.8, 1.5 Hz), 8.02 (1H, brs), 8.74-8.77 (1H, brm) , 10.81 (1H, brs), 12.50 (1H, s).

Example 159
4-{[(4-Fluorobenzoyl) amino] methyl} -N-methyl-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-6-carboxamide 1) N-{[6-Cyano-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] Synthesis of methyl} -4-fluorobenzamide N-{[6-Bromo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1- Benzoxazin-4-yl] methyl} -4-fluorobenzamide (1.0 g, 1.76 mmol), zinc cyanide (414 mg, 3.53 mmol) and tetrakis (triphenylphosphite) N) Palladium (102 mg, 0.088 mmol) in DMF (4.5 mL) was stirred at 100 ° C. for 3 hours. After returning to room temperature, the solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to obtain the desired product (873 mg, 96%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.70 (3H, s), 4.04 (1H, dd, J = 14.6, 4.4 Hz), 4.62 (1H, dd, J = 14.6, 6.8 Hz), 5.12 (1H, d, J = 16.1 Hz), 5.19 (1H, d, J = 16.1 Hz), 6.83 (2H, d, J = 8.8 Hz), 7.18 (2H, d, J = 8.8 Hz), 7.30-7.25 (3H, m), 7.75 (2H, dd, J = 8.8, 5.). 4 Hz), 7.89 (1H, dd, J = 8.8, 2.0 Hz), 8.03 (1H, s), 8.84 (1H, dd, J = 6.8, 4.4 Hz).
2) Synthesis of 4-{[(4-fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-6-carboxylic acid N-{[6-cyano-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-Fluorobenzamide was dissolved in 25% hydrogen bromide-acetic acid (5 mL) and water (1 mL) and stirred at 100 ° C. overnight. The temperature was returned to room temperature, and water was added with stirring. After stirring at room temperature for 30 minutes, the resulting brown solid was dried under reduced pressure to obtain the desired product (317 mg, 55%) as a brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.88 (1H, dd, J = 14.6, 4.4 Hz), 4.57 (1H, dd, J = 14.6, 7.3 Hz) ), 6.98 (1H, d, J = 8.3 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.68 (2H, dd, J = 8.8, 5.4 Hz) 7.92 (1H, dd, J = 8.3, 2.0 Hz), 7.94 (1H, brs), 8.78 (1H, dd, J = 7.3, 4.4 Hz), 11. 07 (1H, s).
3) 4-{[(4-Fluorobenzoyl) amino] methyl} -N-methyl-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-6 Synthesis of Carboxamide 4-{[(4-Fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-6-carboxylic acid (30 mg, 0.073 mmol) and CDI (23.6 mg, 0.15 mmol) were dissolved in THF (230 μL) and DMF (90 μL), stirred at room temperature for 30 minutes, and then methylamine (182 μL, 0.36 mmol) was added. It was. The reaction solution was stirred at room temperature for 30 minutes, diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (10.2 mg, 33%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.76 (3H, d, J = 4.9 Hz), 4.04 (1H, dd, J = 14.4, 5.4 Hz), 4. 43 (1H, dd, J = 14.4, 6.8 Hz), 6.94 (1 H, d, J = 8.8 Hz), 7.23 (2H, t, J = 8.8 Hz), 7.71 (2H, dd, J = 8.8, 5.9 Hz), 7.84 (1H, dd, J = 8.8, 2.0 Hz), 7.94 (1H, brs), 8.35 (1H, q, J = 4.9 Hz), 8.73 (1H, dd, J = 6.8, 5.4 Hz), 10.94 (1H, brs).

Example 160
4-Fluoro-N-{[2-oxo-6- (pyrrolidin-1-ylcarbonyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] Methyl} benzamide 4-{[(4-fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-6-carboxylic acid and The title compound was obtained by the method according to Example 159 using pyrrolidine as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.57-1.70 (2H, m), 1.77-1.84 (2H, m), 3.12-3.17 (2H, brm), 3.36-3.39 (2H, brm), 3.82 (1H, dd, J = 14.6, 3.4 Hz), 4.63 (1H, dd, J = 14.6, 7 .8 Hz), 6.93 (1 H, d, J = 8.3 Hz), 7.23 (2 H, t, J = 8.8 Hz), 7.44 (1 H, s), 7.49 (1 H, dd) , J = 8.3, 2.0 Hz), 7.73 (2H, dd, J = 8.8, 5.4 Hz), 8.79 (1H, dd, J = 7.8, 3.4 Hz), 10.89 (1H, s).

Example 161
N-cyclopentyl 4-{[(4-fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-6-carboxamide 4 -{[(4-Fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-6-carboxylic acid and cyclopentylamine as raw materials And the title compound was obtained by a method according to Example 159.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.45 to 1.58 (4H, brm), 1.66-1.72 (2H, brm), 1.84 to 1.92 (2H, brm), 4.00 (1H, dd, J = 14.6, 4.9 Hz), 4.19 (1H, dd, J = 14.6, 7.3 Hz), 4.50 (1H, dd, J = 14.6, 7.0 Hz), 6.92 (1H, d, J = 8.8 Hz), 7.23 (2H, t, J = 8.8 Hz), 7.71 (2H, dd, J = 8.8, 5.4 Hz), 7.85 (1H, dd, J = 8.8, 2.0 Hz), 7.90 (1H, s), 8.04 (1H, d, J = 7.0 Hz) ), 8.79 (1H, dd, J = 7.3, 4.9 Hz), 10.92 (1H, s).

Example 162
4-{[(4-Fluorobenzoyl) amino] methyl} -N- (4-fluorophenyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -6-Carboxamide 4-{[(4-Fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-6-carvone The title compound was obtained by the method according to Example 159 using acid and 4-fluoroaniline as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.02 (1H, dd, J = 14.6, 5.4 Hz), 4.55 (1H, dd, J = 14.6, 7.3 Hz) ), 7.00 (1H, d, J = 8.3 Hz), 7.18-7.24 (4H, m), 7.70-7.75 (4H, m), 7.98 (1H, dd) , J = 8.8, 2.0 Hz), 8.06 (1H, s), 8.80 (1H, dd, J = 7.3, 5.4 Hz), 10.13 (1H, s), 11 .02 (1H, s).

Example 163
N- (2,3-dihydro-1H-inden-2-yl) -4-{[(4-fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro -2H-3,1-benzoxazine-6-carboxamide 4-{[(4-fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3 , 1-Benzoxazine-6-carboxylic acid and indan-2-amine were used as starting materials, and the title compound was obtained by the method according to Example 159.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.94 (2H, ddd, J = 16.1, 12.2, 6.3 Hz), 3.25 (2H, ddd, J = 16.1) , 7.9, 5.0 Hz), 4.00 (1H, dd, J = 14.6, 4.9 Hz), 4.48 (1H, dd, J = 14.6, 6.8 Hz), 4. 64-4.72 (1H, m), 6.92 (1H, d, J = 8.3 Hz), 7.14-7.25 (6H, m), 7.68 (2H, dd, J = 8) .8, 5.4 Hz), 7.87 (1H, dd, J = 8.3, 2.0 Hz), 7.94 (1H, s), 8.45 (1H, d, J = 7.3 Hz) , 8.77 (1H, dd, J = 6.8, 4.9 Hz), 10.94 (1H, s).

Example 164
N- (2,2-difluoroethyl) -4-{[(4-fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1- Benzoxazine-6-carboxamide 4-{[(4-fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-6 -The title compound was obtained by the method according to Example 159 using carboxylic acid and 2,2-difluoroethylamine as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.62-3.71 (2H, m), 4.06 (1H, dd, J = 14.6, 4.9 Hz), 4.43 ( 1H, dd, J = 14.6, 6.8 Hz), 6.10 (1H, tt, J = 56.1, 4.0 Hz), 6.96 (1H, d, J = 8.8 Hz), 7 .23 (2H, t, J = 8.8 Hz), 7.72 (2H, dd, J = 8.8, 5.4 Hz), 7.90 (1H, dd, J = 8.8, 2.0 Hz) ), 7.99 (1H, s), 8.73-8.78 (2H, m), 10.99 (1H, s).

Example 165
4-{[(4-Fluorobenzoyl) amino] methyl} -2-oxo-N- (2,2,2-trifluoroethyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3 , 1-Benzoxazine-6-carboxamide 4-{[(4-fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz The title compound was obtained by a method according to Example 159 using oxazine-6-carboxylic acid and 2,2,2-trifluoroethylamine as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.02-4.16 (3H, m), 4.45 (1H, dd, J = 14.1, 6.8 Hz), 6.97 ( 1H, d, J = 8.3 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.72 (2H, dd, J = 8.8, 5.4 Hz), 7.92 (1H , Dd, J = 8.3, 2.0 Hz), 8.01 (1H, s), 8.75 (1H, dd, J = 6.8, 4.9 Hz), 8.99 (1H, t, J = 6.1 Hz), 11.01 (1H, s).

Example 166
4-{[(4-Fluorobenzoyl) amino] methyl} -2-oxo-N-((3R) -tetrahydrofuran-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3 , 1-Benzoxazine-6-carboxamide 4-{[(4-fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz The title compound was obtained by a method according to Example 159 using oxazine-6-carboxylic acid and (3R) -aminotetrahydrofuran p-toluenesulfonate as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.83-1.93 (1H, m), 2.10-2.20 (1H, m), 3.54-3.61 (1H, m), 3.67-3.73 (1H, m), 3.81-3.89 (2H, m), 4.02 (1H, dd, J = 14.4, 4.9 Hz), 4. 41-4.45 (1H, brm), 4.48 (1H, dd, J = 14.4, 6.8 Hz), 6.93 (1H, d, J = 8.3 Hz), 7.23 (2H , T, J = 8.8 Hz), 7.70-7.74 (2H, m), 7.87 (1H, dd, J = 8.3, 1.5 Hz), 7.94 (1H, s) , 8.35 (1H, d, J = 6.3 Hz), 8.77 (1H, dd, J = 6.8, 4.9 Hz), 10.95 (1H, s).

Example 167
N-bicyclo [2.2.1] heptan-2-yl-4-{[(4-fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H -3,1-Benzoxazine-6-carboxamide 4-{[(4-fluorobenzoyl) amino] methyl} -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1 -The title compound was obtained by the method according to Example 159 using benzoxazine-6-carboxylic acid and bicyclo [2.2.1] heptan-2-amine as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.07-1.16 (1H, m), 1.23-1.64 (6H, m), 1.87-1.94 (1H, m), 2.16-2.19 (1H, brm), 2.37-2.41 (1H, brm), 3.93 (1H, td, J = 14.1, 4.4 Hz), 4. 02-4.09 (1H, brm), 4.57 (1H, td, J = 14.9, 7.6 Hz), 6.93 (1H, dd, J = 8.3, 2.4 Hz), 7 .22 (2H, td, J = 8.8, 3.4 Hz), 7.68-7.73 (2H, m), 7.83-7.91 (3H, m), 8.81-8. 85 (1H, m), 10.93 (1H, s).

Example 168
N-{[6-Cyano-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide in Example 159 Synthesized N-{[6-cyano-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] The title compound was obtained by deprotecting methyl} -4-fluorobenzamide by a method according to Example 125.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.95 (1H, dd, J = 14.6, 3.4 Hz), 4.57 (1H, dd, J = 14.6, 6.8 Hz) ), 7.03 (1H, d, J = 8.8 Hz), 7.26 (2H, t, J = 8.8 Hz), 7.73 (2H, dd, J = 8.8, 5.4 Hz) , 7.85 (1H, dd, J = 8.8, 1.5 Hz), 7.95 (1H, s), 8.77-8.80 (1H, m).

Example 169
4-fluoro-N-{[2-oxo-6- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -4- (trifluoromethyl) -1, 4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide N-{[6-cyano-2-oxo-4- (trifluoromethyl) -1,4- synthesized in Example 159 To a solution of dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide (50 mg, 0.127 mmol) in ethanol (0.5 mL) was added hydroxylamine (50% aqueous solution, 40 μL). Stir at room temperature overnight. The solution was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. The residue was dissolved in dioxane (1 mL) and CDI (41 mg, 0.25 mmol) was added with stirring at room temperature. The reaction solution was stirred at 90 ° C. for 3 hours and then returned to room temperature. The solution was diluted with ethyl acetate, washed successively with water, 1N hydrochloric acid and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the residue was crystallized from ethanol and water to obtain the desired product (18 mg, 31%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.02 (1H, dd, J = 14.6, 4.9 Hz), 4.44 (1H, dd, J = 14.6, 6.8 Hz) ), 7.05 (1H, d, J = 8.5 Hz), 7.23 (2H, t, J = 8.8 Hz), 7.71 (2H, dd, J = 8.8, 5.4 Hz) 7.82 (1H, dd, J = 8.5, 2.0 Hz), 7.90 (1H, brs), 8.77 (1H, dd, J = 6.8, 4.9 Hz), 11. 12 (1H, s).

Example 170
4-Fluoro-N-{[2-oxo-6- (1H-tetrazol-5-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide N-{[6-cyano-2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl synthesized in Example 159 } -4-Fluorobenzamide (30 mg, 0.076 mmol), sodium azide (24.8 mg, 0.38 mmol) and ammonium chloride (20.4 mg, 0.38 mmol) were dissolved in DMF (0.5 mL). The mixture was stirred at 12 ° C. for 12 hours. Water was added to the solution, extracted twice with ethyl acetate-ethanol, and the resulting organic layer was dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by reverse phase HPLC to obtain the desired product (3.4 mg, 10%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.99-4.05 (1H, m), 4.52 (1H, dd, J = 14.1, 7.3 Hz), 7.09 ( 1H, d, J = 8.5 Hz), 7.20 (2H, t, J = 8.8 Hz), 7.68 (2H, dd, J = 8.8, 5.4 Hz), 8.04 (1H , Dd, J = 8.5, 1.5 Hz), 8.12 (1H, brs), 8.81 (1H, dd, J = 7.3, 4.9 Hz), 11.08 (1H, s) .

Example 171
4-Fluoro-N-{[2-oxo-6- (1H-1,2,4-triazol-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1- Benzoxazin-4-yl] methyl} benzamide 1) N-{[6-iodo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3 , 1-Benzoxazin-4-yl] methyl} -4-fluorobenzamide N-{[6-Bromo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1, 4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide (1.18 g, 2.08 mmol), copper (I) iodide (79 mg, 0.416 mmol) and iodide Nat N, N′-dimethylethylenediamine (89 μL, 0.832 mmol) was added at room temperature in a dioxane (4.2 mL) solution of lithium (624 mg, 4.16 mmol). The reaction solution was heated and stirred at 110 ° C. for 5 hours. After returning to room temperature, the solution was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting solid was washed with hexane and ethyl acetate to obtain the desired product (995 mg, 78%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.68 (3H, s), 3.87 (1H, dd, J = 14.6, 3.9 Hz), 4.61 (1H, dd, J = 14.6, 7.8 Hz), 5.02 (1H, d, J = 16.6 Hz), 5.10 (1H, d, J = 16.6 Hz), 6.83 (2H, d, J = 8.8 Hz), 6.87 (1H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 7.25 (2H, t, J = 8.8 Hz) , 7.68 (1H, dd, J = 8.8, 2.0 Hz), 7.72-7.77 (3H, m), 8.85 (1H, dd, J = 7.8, 3.9 Hz) ).
2) 4-Fluoro-N-{[2-oxo-6- (1H-1,2,4-triazol-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3, Synthesis of 1-benzoxazin-4-yl] methyl} benzamide N-{[6-Iodo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H -3,1-Benzoxazin-4-yl] methyl} -4-fluorobenzamide (50 mg, 0.081 mmol), 1,2,4-triazole (16.9 mg, 0.244 mmol), potassium phosphate (25. 9 mg, 0.122 mmol), N, N′-dimethylethylenediamine (6.9 μL, 0.065 mmol) and copper (I) iodide (3.1 mg, 0.016 mmol) in DMF (0 .4 mL) solution was heated and stirred at 110 ° C. for 1 hour. After returning to room temperature, the solution was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The 4-methoxybenzyl group was deprotected by subjecting the residue to conditions according to Example 154 to obtain the desired product (8.0 mg, 23%) as a pale white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.99 (1H, dd, J = 14.6, 4.4 Hz), 4.59 (1H, dd, J = 14.6, 6.8 Hz) ), 7.05 (1H, d, J = 8.8 Hz), 7.21 (2H, t, J = 8.8 Hz), 7.70 (2H, dd, J = 8.8, 5.4 Hz) , 7.85 (1H, dd, J = 8.8, 2.4 Hz), 7.95 (1H, s), 8.23 (1H, s), 8.81 (1H, dd, J = 6. 8, 4.4 Hz), 9.18 (1 H, s), 10.94 (1 H, s).

Example 172
N-{[6- (Benzoylamino) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide N -{[6-Iodo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl}- The title compound was obtained by a method according to Example 171 using 4-fluorobenzamide and benzamide as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.00 (1H, dd, J = 14.6, 4.9 Hz), 4.33 (1H, dd, J = 14.6, 6.8 Hz) ), 6.89 (1H, d, J = 8.3 Hz), 7.23 (2H, t, J = 8.8 Hz), 7.50-7.54 (2H, m), 7.56-7 .60 (1H, m), 7.75 (2H, dd, J = 8.8, 5.4 Hz), 7.83 (1H, dd, J = 8.8, 2.4 Hz), 7.86 ( 1H, s), 7.92-7.94 (2H, m), 8.76 (1H, dd, J = 6.8, 4.9 Hz), 10.30 (1H, s), 10.65 ( 1H, s).

Example 173
4-Fluoro-N-{[2-oxo-6- (2-oxo-1,3-oxazolidine-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1- Benzoxazin-4-yl] methyl} benzamide N-{[6-iodo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1 -Benzoxazin-4-yl] methyl} -4-fluorobenzamide and 1,3-oxazolidine-2-one were used as starting materials, and the title compound was obtained by the method according to Example 171.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.85 (1H, dd, J = 14.6, 4.4 Hz), 3.95 (1H, q, J = 8.3 Hz), 4. 05 (1H, q, J = 8.3 Hz), 4.42 (2H, t, J = 8.3 Hz), 4.57 (1H, dd, J = 14.6, 7.8 Hz), 6.92 (1H, d, J = 8.8 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.45 (1H, d, J = 2.4 Hz), 7.68 (1H, dd, J = 8.8, 2.4 Hz), 7.74 (2H, dd, J = 8.8, 5.9 Hz), 8.79 (1H, dd, J = 7.8, 4.4 Hz), 10 .68 (1H, s).
4-Fluoro-N-{[(4S ^* )-2-oxo-6- (2-oxo-1,3-oxazolidin-3-yl) -4- (trifluoromethyl) -1,4-dihydro-2H -3,1-Benzoxazin-4-yl] methyl} benzamide 4-fluoro-N-{[2-oxo-6- (2-oxo-1,3-oxazolidine-3-yl) -4- (trifluoro Methyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl] methyl} benzamide was subjected to optical resolution with HPLC (chiral pack AD-H, n-hexane: ethanol = 3: 1). The fraction eluted in the latter half was concentrated to obtain the desired product.

Example 174
4-Fluoro-N-{[6- (3-methyl-2-oxazolidine-1-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide N-{[6-iodo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz The title compound was obtained by a method according to Example 171 using oxazin-4-yl] methyl} -4-fluorobenzamide and 1-methylimidazolidin-2-one as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.73 (3H, s), 3.41 (2H, t, J = 8.3 Hz), 3.71 (2H, dt, J = 12. 7, 8.3 Hz), 3.84 (1 H, dd, J = 14.4, 4.1 Hz), 4.53 (1 H, dd, J = 14.6, 7.8 Hz), 6.85 (1 H , D, J = 8.8 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.40 (1H, s), 7.70-7.75 (3H, m), 8.77. (1H, dd, J = 7.8, 4.1 Hz), 10.56 (1H, s).

Example 175
4-Fluoro-N-{[2-oxo-6- (2-oxopyridin-1 (2H) -yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide N-{[6-iodo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz The title compound was obtained by a method according to Example 171 using oxazin-4-yl] methyl} -4-fluorobenzamide and 2-hydroxypyridine as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.86 (1H, dd, J = 14.6, 4.4 Hz), 4.59 (1H, dd, J = 14.6, 7.8 Hz) ), 6.34 (1H, td, J = 6.8, 1.5 Hz), 6.47 (1H, dd, J = 9.8, 1.5 Hz), 6.97 (1H, d, J = 9.3 Hz), 7.24 (2H, t, J = 8.8 Hz), 7.45-7.52 (4H, m), 7.74 (2H, dd, J = 8.8, 5.4 Hz) ), 8.82 (1H, dd, J = 7.8, 4.4 Hz), 10.90 (1H, s).

Example 176
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} benzamide N-{[6-Iodo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine-4- The title compound was obtained by a method according to Example 171 using [Il] methyl} -4-fluorobenzamide and pyrazole as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.94 (1H, dd, J = 14.4, 4.9 Hz), 4.63 (1H, dd, J = 14.4, 7.3 Hz) ), 6.55 (1H, t, J = 2.4 Hz), 7.00 (1H, d, J = 8.8 Hz), 7.21 (2H, t, J = 8.8 Hz), 7.69 −7.73 (3H, m), 7.82-7.86 (2H, m), 8.39 (1H, d, J = 2.4 Hz), 8.83 (1H, dd, J = 7. 3, 4.9 Hz), 10.84 (1 H, s).
4-Fluoro-N-{[(4S ^* )-2-oxo-6- (1H-pyrazol-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz Oxazin-4-yl] methyl} benzamide 4-fluoro-N-{[2-oxo-6- (1H-pyrazol-1-yl) -4- (trifluoromethyl) -1,4-dihydro-2H-3 , 1-Benzoxazin-4-yl] methyl} benzamide is optically resolved by HPLC (Chiral Pack AD-H, n-hexane: ethanol = 4: 1), and the fraction eluted in the latter half is concentrated for the purpose. I got a thing.

Example 177
4-Fluoro-N-{[6- (4-methyl-1H-pyrazol-1-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide N-{[6-iodo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz The title compound was obtained by a method according to Example 171 using oxazin-4-yl] methyl} -4-fluorobenzamide and 4-methylpyrazole as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.09 (3H, d, J = 6.3 Hz), 3.96 (1H, dd, J = 14.6, 4.4 Hz), 4. 62 (1H, dd, J = 14.6, 6.8 Hz), 6.99 (1H, d, J = 8.8 Hz), 7.23 (2H, t, J = 8.8 Hz), 7.54 (1H, s), 7.72 (2H, dd, J = 8.8, 5.4 Hz), 7.78-7.80 (2H, m), 8.18 (1H, s), 8.84 (1H, dd, J = 6.8, 4.4 Hz), 10.83 (1H, s).

Example 178
4-Fluoro-N-{[6- (3-methyl-1H-pyrazol-1-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazine -4-yl] methyl} benzamide N-{[6-iodo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz The title compound was obtained by a method according to Example 171 using oxazin-4-yl] methyl} -4-fluorobenzamide and 3-methylpyrazole as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.26 (3H, s), 3.99 (1H, dd, J = 14.6, 4.9 Hz), 4.62 (1H, dd, J = 14.6, 7.3 Hz), 6.34 (1H, d, J = 2.4 Hz), 6.98 (1H, d, J = 8.8 Hz), 7.23 (2H, t, J = 8.8 Hz), 7.73 (2H, dd, J = 8.8, 5.4 Hz), 7.78-7.81 (2H, m), 8.26 (1H, d, J = 2. 4 Hz), 8.85 (1 H, dd, J = 7.3, 4.9 Hz), 10.82 (1 H, s).

Example 179
N-{[6- (3-Amino-1H-pyrazol-1-yl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-4-yl ] Methyl} -4-fluorobenzamide N-{[6-Iodo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benz The title compound was obtained by a method according to Example 171 using oxazin-4-yl] methyl} -4-fluorobenzamide and 3-aminopyrazole as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.96 (1H, dd, J = 14.6, 4.4 Hz), 4.56 (1H, dd, J = 14.6, 7.3 Hz) ), 5.94 (1H, d, J = 2.4 Hz), 6.95 (1H, d, J = 8.3 Hz), 7.23 (2H, t, J = 8.8 Hz), 7.67. −7.75 (4H, m), 8.15 (1H, d, J = 2.4 Hz), 8.85 (1H, dd, J = 7.3, 4.4 Hz), 10.78 (1H, s).

Example 180
4-fluoro-N-{[2-oxo-4- (trifluoromethyl) -6- [3- (trifluoromethyl) -1H-pyrazol-1-yl] -1,4-dihydro-2H-3, 1-Benzoxazin-4-yl] methyl} benzamide N-{[6-iodo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3 , 1-Benzoxazin-4-yl] methyl} -4-fluorobenzamide and 3- (trifluoromethyl) pyrazole as starting materials, the title compound was obtained by the method according to Example 171.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.99 (1H, dd, J = 14.6, 4.4 Hz), 4.65 (1H, dd, J = 14.6, 7.3 Hz) ), 7.06 (1H, d, J = 8.8 Hz), 7.08 (1H, d, J = 2.4 Hz), 7.23 (2H, t, J = 8.8 Hz), 7.73 (2H, dd, J = 8.8, 5.4 Hz), 7.89 (1H, dd, J = 8.8, 2.4 Hz), 7.94 (1H, brs), 8.63 (1H, brs), 8.86 (1H, dd, J = 7.3, 4.4 Hz), 10.97 (1H, s).

Example 181
4-Fluoro-N-{[6-[(3S) -3-hydroxy-2-oxopyrrolidin-1-yl] -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H-3 , 1-Benzoxazin-4-yl] methyl} benzamide N-{[6-iodo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,4-dihydro-2H- The title compound was obtained by a method according to Example 171 using 3,1-benzoxazin-4-yl] methyl} -4-fluorobenzamide and (3S) -3-hydroxypyrrolidin-2-one as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.76-1.87 (1H, m), 2.35-2.44 (1H, m), 3.57-3.75 (1H, m), 3.86 (1H, td, J = 14.1, 3.9 Hz), 4.25-4.31 (1H, m), 4.58 (1H, ddd, J = 23.4, 14). .1, 7.8 Hz), 5.76 (1 H, brs), 6.92 (1 H, d, J = 8.8 Hz), 7.24 (2 H, t, J = 8.8 Hz), 7.46 (1H, s), 7.73-7.77 (3H, m), 8.78-8.83 (1H, m), 10.71 (1H, d, J = 3.4 Hz).

Example 182
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} benzamide 1) Synthesis of 6-bromo-4-hydroxy-1- (4-methoxybenzyl) -4- (trifluoromethyl) -3,4-dihydroquinazolin-2 (1H) -one 1- {5-bromo-2 -[(4-Methoxybenzyl) amino] phenyl} -2,2,2-trifluoroethanone (5.0 g, 12.9 mmol) was dissolved in a mixed solvent of acetic acid (20 mL) and water (2 mL), and the solution was dissolved. Sodium cyanate (85%, 2.96 g, 38.7 mmol) was added with heating and stirring at 60 ° C. The reaction solution was heated and stirred at 60 ° C. overnight, cooled to room temperature, and water (100 mL) was added. After stirring at room temperature for 1 hour, the resulting solid was collected by filtration and washed with water. The solid was dried and crystallized from ethyl acetate-hexane to obtain the desired product (4.53 g, 81%) as a pale green solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.77 (3H, s), 4.92 (1H, d, J = 17.1 Hz), 5.19 (1H, d, J = 17.1 Hz) , 6.00 (1H, s), 6.76 (1H, d, J = 8.8 Hz), 6.84 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.42 (1H, dd, J = 8.8, 2.4 Hz), 7.77 (1H, d, J = 2.4 Hz).
2) Synthesis of 6-bromo-1- (4-methoxybenzyl) -4- (nitromethyl) -4- (trifluoromethyl) -3,4-dihydroquinazolin-2 (1H) -one 6-bromo-4- Hydroxy-1- (4-methoxybenzyl) -4- (trifluoromethyl) -3,4-dihydroquinazolin-2 (1H) -one (3.0 g, 6.96 mmol) and p-toluenesulfonic acid monohydrate Of the product (13.2 mg, 0.07 mmol) was heated and stirred in xylene (30 mL) at 150 ° C for 3 hours. After cooling to room temperature, nitromethane (1.88 mL, 35 mmol) and N, N-diisopropylethylamine (1.33 mL, 7.7 mmol) were added, and the reaction solution was heated and stirred at 100 ° C. for 1 hour. The reaction solution was cooled to 0 ° C., hexane (20 mL) was gradually added with stirring, and the mixture was stirred at 0 ° C. for 2 hours. The resulting solid was collected by filtration and washed with hexane to obtain the desired product (3.29 g, 99%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.77 (3H, s), 4.90 (1H, d, J = 13.2 Hz), 5.06 (1H, d, J = 13.2 Hz) 5.10 (2H, brs), 6.77 (1H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 7.06 (1H, s), 7 .13 (2H, d, J = 8.8 Hz), 7.39 (1H, dd, J = 8.8, 2.0 Hz), 7.43 (1H, brs).
3) Synthesis of 4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -3,4-dihydroquinazolin-2 (1H) -one 6-Bromo-1 -(4-Methoxybenzyl) -4- (nitromethyl) -4- (trifluoromethyl) -3,4-dihydroquinazolin-2 (1H) -one (1.0 g, 2.1 mmol), iron (294 mg, 5 .3 mmol), ammonium chloride (562 mg, 10.5 mmol) was stirred in methanol (5 mL) and water (5 mL) and heated to reflux overnight. The reaction solution was cooled to room temperature, methanol (10 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solid was filtered off, the mother liquor was concentrated, and the residue was washed successively with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain the desired product (958 mg, quant.) As a colorless foamy solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.11 (1H, d, J = 13.7 Hz), 3.42 (1H, d, J = 13.7 Hz), 3.70 (3H, s), 4.90 (1H, d, J = 16.1 Hz), 5.16 (1H, d, J = 16.1 Hz), 6.85 (1H, d, J = 8.8 Hz), 6. 86 (2H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.8, 2.4 Hz), 7.57 (1H, s), 8.06 (1H, brs).
4) N-{[6-Bromo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} -4 -Synthesis of fluorobenzamide 4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -4- (trifluoromethyl) -3,4-dihydroquinazolin-2 (1H) -one (710 mg, 1 .60 mmol), 4-fluorobenzoic acid (246 mg, 1.76 mmol), hydroxybenzotriazole monohydrate (245 mg, 1.60 mmol) and triethylamine (0.22 mL, 1.6 mmol) in DMF (5 mL) Under stirring at 0 ° C., 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (368 mg, 1.9 mmol) Was added in small portions. After stirring the reaction solution at room temperature overnight, water was slowly added to the reaction solution with stirring. After solid began to precipitate, excess water was further added and stirred at room temperature for 2 hours. The solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the desired product (815 mg, 90%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.70 (3H, s), 3.87 (1H, dd, J = 14.1, 3.9 Hz), 4.43 (1H, dd, J = 14.1, 6.8 Hz), 4.92 (1H, d, J = 16.6 Hz), 5.16 (1H, d, J = 16.6 Hz), 6.83 (2H, d, J = 8.8 Hz), 6.84 (1H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.27 (2H, t, J = 9.3 Hz) , 7.44 (1H, dd, J = 8.8, 2.4 Hz), 7.56 (1H, brs), 7.76 (1H, d, J = 8.8 Hz), 7.77 (1H, d, J = 8.8 Hz), 8.13 (1H, s), 8.64 (1H, dd, J = 6.8, 3.9 Hz).
5) Synthesis of N-{[6-bromo-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} -4-fluorobenzamide N-{[ 6-Bromo-1- (4-methoxybenzyl) -2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} -4-fluorobenzamide (260 mg, To an acetonitrile (6 mL) solution of 0.46 mmol), an aqueous solution (1 mL) of ceric ammonium nitrate (755 mg, 1.38 mmol) was added dropwise at room temperature with stirring. The reaction solution was stirred at room temperature for 4 hours. Sodium pyrosulfite was added to the reaction solution, and after stirring for 30 minutes, the solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2/1) to obtain the desired product (150 mg, 73%) as a white solid.
¹ H-NMR (400 MHz, CD ₃ OD) δ: 3.88 (1H, d, J = 14.4 Hz), 4.43 (1H, d, J = 14.4 Hz), 6.80 (1H, d , J = 8.7 Hz), 7.08-7.15 (2H, m), 7.44 (1H, dd, J = 8.7, 2.1 Hz), 7.61 (1H, brs), 7 .65-7.71 (2H, m).
6) 4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl } Synthesis of benzamide N-{[6-Bromo-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} -4-fluorobenzamide (50 mg, 0 .112 mmol), 1H-pyrazole-5-boronic acid (29 mg, 0.23 mmol), palladium chloride 1,1-bis (diphenylphosphino) ferrocene complex (18.3 mg, 0.022 mmol) and potassium phosphate trihydrate The Japanese product (60 mg, 0.23 mmol) was suspended in DMF (0.5 mL) and water (0.05 mL), and the mixed solution was subjected to microwave irradiation. , And stirred at 120 ° C. for 30 minutes. After cooling, the solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by reverse phase HPLC to obtain the desired product (10 mg, 21%) as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.97 (1 H, d, J = 13.7 Hz), 4.36 (1 H, dd, J = 13.7, 6.3 Hz), 6. 60 (1H, d, J = 2.4 Hz), 6.88 (1H, d, J = 8.3 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.76-7.62 (6H, m), 8.58-8.60 (1H, brm), 9.71 (1H, s).
4-Fluoro-N-{[(4S ^* ) 2-oxo-6- (1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl ] Methyl} benzamide 4-fluoro-N-{[2-oxo-6- (1H-pyrazol-5-yl) -4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl Methyl} benzamide was subjected to optical resolution with HPLC (Chiral Pack AD-H, n-hexane: 2-propanol = 3: 1), and the fraction eluted in the latter half was concentrated to obtain the desired product.

Example 183
N-{[6-Chloro-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} benzamide 1- (2-amino-5-chlorophenyl)- The title compound was obtained by a method according to Example 182 using 2,2,2-trifluoroethanone and benzoic acid as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.82 (1H, dd, J = 14.1, 4.4 Hz), 4.35 (1H, dd, J = 14.1, 7.3 Hz) ), 6.85 (1H, d, J = 8.8 Hz), 7.33 (1H, dd, J = 8.8, 2.4 Hz), 7.39-7.42 (4H, m), 7 .47-7.51 (1H, m), 7.64-7.66 (3H, m), 8.55 (1H, dd, J = 7.3, 4.4 Hz), 9.78 (1H, s).

Example 184
2-chloro-N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} benzamide 1- (2-amino-5 -Chlorophenyl) -2,2,2-trifluoroethanone and 2-chlorobenzoic acid were used as starting materials, and the title compound was obtained by the method according to Example 182.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.62 (1H, dd, J = 14.1, 2.4 Hz), 4.45 (1H, dd, J = 14.1, 8.3 Hz) ), 6.85 (1H, d, J = 8.3 Hz), 7.05 (1H, dd, J = 6.8, 1.5 Hz), 7.27-7.35 (3H, m), 7 35-7.39 (2H, m), 7.77 (1H, s), 8.81 (1H, dd, J = 8.3, 2.4 Hz), 9.75 (1H, s).

Example 185
3-chloro-N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} benzamide 1- (2-amino-5 The title compound was obtained by the method according to Example 182 using -chlorophenyl) -2,2,2-trifluoroethanone and 3-chlorobenzoic acid as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.83 (1H, dd, J = 14.1, 4.4 Hz), 4.34 (1H, dd, J = 14.1, 7.3 Hz) ), 6.85 (1H, d, J = 8.8 Hz), 7.34 (1H, dd, J = 8.5, 2.2 Hz), 7.36 (1H, brs), 7.45 (1H) , T, J = 7.8 Hz), 7.56-7.58 (1H, m), 7.60-7.63 (1H, m), 7.67 (1H, t, J = 1.7 Hz) , 7.70 (1H, d, J = 2.0 Hz), 8.69 (1H, dd, J = 7.3, 4.4 Hz), 9.79 (1H, s).

Example 186
4-chloro-N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} benzamide 1- (2-amino-5 The title compound was obtained by the method according to Example 182 using -chlorophenyl) -2,2,2-trifluoroethanone and 4-chlorobenzoic acid as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.82 (1 H, dd, J = 14.1, 3.9 Hz), 4.34 (1 H, dd, J = 14.1, 6.8 Hz) ), 6.85 (1H, d, J = 8.8 Hz), 7.33 (1H, dd, J = 8.8, 2.2 Hz), 7.37 (1H, brs), 7.49 (2H) , D, J = 8.3 Hz), 7.68 (2H, d, J = 8.3 Hz), 7.68 (1H, brs), 8.64 (1H, brs), 9.78 (1H, s) ).

Example 187
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} 4-fluorobenzamide 1- (2-amino-5 The title compound was obtained by a method according to Example 182 using chlorophenyl) -2,2,2-trifluoroethanone and 4-fluorobenzoic acid as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.84 (1H, d, J = 14.6 Hz), 4.34 (1H, d, J = 14.6 Hz), 6.86 (1H, d, J = 8.8 Hz), 7.26 (2H, t, J = 8.8 Hz), 7.34 (1H, dd, J = 8.8, 2.0 Hz), 7.39 (1H, s ), 7.69 (1H, brs), 7.75 (2H, dd, J = 8.8, 5.4 Hz), 8.58-8.62 (1H, m), 9.79 (1H, s) ).
¹ H-NMR (DMSO-D ₆ ) δ: 9.79 (1H, s), 8.62-8.58 (1H,
N-{[(4S ^* )-6-chloro-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} 4-fluorobenzamide N-{[ 6-Chloro-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} 4-fluorobenzamide was HPLC (chiral pack AD-H, n-hexane: 2-Propanol = 3: 1) was optically resolved, and the fraction eluted in the latter half was concentrated to obtain the desired product.

Example 188
4-fluoro-N-{[2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} benzamide 1- (2-aminophenyl) -2,2 , 2-trifluoroethanone and 4-fluorobenzoic acid were used as starting materials, and the title compound was obtained by the method according to Example 182.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.91 (1H, d, J = 14.1 Hz), 4.29 (1H, d, J = 14.1 Hz), 6.86 (1H, d, J = 8.3 Hz), 6.93 (1H, t, J = 7.8 Hz), 7.23-7.28 (3H, m), 7.33 (1H, d, J = 7.8 Hz) ), 7.58 (1H, brs), 7.75 (2H, dd, J = 8.8, 5.4 Hz), 8.49-8.52 (1H, brm), 9.64 (1H, brs) ).

Example 189
N-{[6-chloro-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} 4-fluorobenzenesulfonamide 1- (2-amino- Using 5-chlorophenyl) -2,2,2-trifluoroethanone and (4-fluorophenyl) sulfonyl chloride as raw materials, the title compound was obtained by a method according to Example 99 and Example 182.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.35 (1H, d, J = 13.2 Hz), 3.72 (1H, d, J = 13.2 Hz), 6.86 (1H, d, J = 8.3 Hz), 7.19 (1H, brs), 7.34-7.43 (3H, m), 7.66 (1H, brs), 7.85 (2H, dd, J = 8.8, 5.4 Hz), 8.02 (1H, brs), 9.77 (1H, brs).

Example 190
4-Fluoro-N-{[2-oxo-6- (1H-pyrazol-4-yl) -4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} benzamide 1- (2-amino-5-chlorophenyl) -2,2,2-trifluoroethanone and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H The title compound was obtained by the method according to Example 182 using pyrazole as a starting material.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.86 (1H, dd, J = 13.9, 3.9 Hz), 4.48 (1H, dd, J = 13.9, 7.8 Hz) ), 6.82 (1H, d, J = 8.3 Hz), 7.21 (2H, t, J = 8.8 Hz), 7.46 (1H, dd, J = 8.3, 2.0 Hz) 7.53 (2H, d, J = 2.4 Hz), 7.72 (2H, dd, J = 8.8, 5.4 Hz), 7.80 (1H, brs), 8.02 (1H, brs), 8.57 (1H, dd, J = 7.8, 3.9 Hz), 9.60 (1H, s), 12.86 (1H, s).

Example 191
N-{[6-Bromo-3-methyl-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} -4-fluorobenzamide 1) 6- Bromo-1- (4-methoxybenzyl) -3-methyl-4- (nitromethyl) -4- (trifluoromethyl) -3,4-dihydroquinazolin-2 (1H) -one 6-bromo-1- (4 -Methoxybenzyl) -4- (nitromethyl) -4- (trifluoromethyl) -3,4-dihydroquinazolin-2 (1H) -one (192.1 mg, 0.405 mmol) dissolved in DMF (2.0 ml) Sodium hydride (40.5 mg, 1.013 mmol) and methyl iodide (76 μL, 1.215 mmol) were sequentially added to the reaction solution at room temperature. The reaction solution was stirred at 50 ° C. overnight, then cooled to room temperature, ethyl acetate and water were added, and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated, washed with saturated brine, and dried over magnesium sulfate. After filtering the desiccant, the solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate / hexane) to give the desired 6-bromo-1- (4-methoxybenzyl) -3-methyl-4- (nitromethyl) -4- (trifluoromethyl)- 3,4-Dihydroquinazolin-2 (1H) -one (44.3 mg, 22.4%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.36 (3H, s), 3.77 (3H, s), 5.12 (2H, s), 5.28 (1H, d, J = 14) .6 Hz), 5.39 (1H, d, J = 14.6 Hz), 6.73 (1 H, d, J = 9.0 Hz), 6.85 (2H, d, J = 8.8 Hz), 7 .11 (2H, d, J = 8.8 Hz), 7.37 (1H, dd, J = 9.0, 2.1 Hz), 7.45 (1H, brs)
2) 4- (Aminomethyl) -6-bromo-1- (4-methoxybenzyl) -3-methyl-4- (trifluoromethyl) -3,4-dihydroquinazolin-2 (1H) -one 6-bromo -1- (4-methoxybenzyl) -3-methyl-4- (nitromethyl) -4- (trifluoromethyl) -3,4-dihydroquinazolin-2 (1H) -one (217.3 mg, 0.445 mmol) Was dissolved in THF (0.9 ml), methanol (0.9 ml) and water (0.5 ml), and iron (497 mg, 8.9 mmol) and ammonium chloride (476 mg, 8.9 mmol) were added to the reaction solution at room temperature. Added sequentially. The reaction solution was stirred at 90 ° C. for 2.5 hours, cooled to room temperature, and insolubles were filtered through celite. After the solvent was distilled off under reduced pressure, chloroform and saturated sodium bicarbonate were added to the residue, and the mixture was stirred at room temperature. The organic layer was separated, washed with saturated brine, and dried over magnesium sulfate. After filtering the desiccant, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 1: 4), and the desired 4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -3-methyl-4- (tri Fluoromethyl) -3,4-dihydroquinazolin-2 (1H) -one (148.3 mg, 72.7%) was obtained as a white solid.
3) N-{[6-Bromo-1- (4-methoxy-benzyl) -3-methyl-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl ] Synthesis of methyl} -4-fluorobenzamide 4- (aminomethyl) -6-bromo-1- (4-methoxybenzyl) -3-methyl-4- (trifluoromethyl) -3,4-dihydroquinazoline-2 (1H) -one (36.8 mg, 0.080 mmol) was dissolved in DMF (1.0 ml) and 4-fluorobenzoic acid (28.1 mg, 0.201 mmol), 1- (3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (46.2 mg, 0.241 mmol), 1-hydroxybenzotriazole monohydrate (36.9 mg, 0.241 mmol), pyridine (0 0.032 ml, 0.402 mmol) was sequentially added to the reaction solution at room temperature. The reaction solution was stirred at room temperature overnight, chloroform and water were added, and the mixture was stirred at room temperature. The organic layer was separated, washed with saturated brine, and dried over magnesium sulfate. After filtering the desiccant, the solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography (chloroform / methanol = 1: 10), and the desired N-{[6-bromo-1- (4-methoxybenzyl) -3-methyl-2-oxo-4- ( Trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} -4-fluorobenzamide (33.9 mg, 73%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.28 (3H, d, J = 1.0 Hz), 3.77 (3H, s), 4.35 (1H, dd, J = 15.1, 4.9 Hz), 4.57 (1H, dd, J = 15.1, 5.9 Hz), 4.99 (1H, d, J = 16.6 Hz), 5.24 (1H, d, J = 16) .6 Hz), 5.77 (1H, brs), 6.84-6.78 (3H, m), 7.06-7.10 (2H, m), 7.14 (2H, d, J = 8) .8 Hz), 7.39 (1 H, dd, J = 8.8, 2.0 Hz), 7.52 (1 H, s), 7.56-7.61 (2 H, m).
4) Synthesis of N-{[6-bromo-3-methyl-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl} -4-fluorobenzamide N-{[6-Bromo-1- (4-methoxy-benzyl) -3-methyl-2-oxo-4- (trifluoromethyl) -1,2,3,4-tetrahydroquinazolin-4-yl] methyl } -4-Fluorobenzamide (9.6 mg, 0.017 mmol) was dissolved in acetonitrile (1.0 ml) and water (0.25 ml), and cerium ammonium nitrate (27.2 mg, 0.050 mmol) was reacted under ice cooling. Added to the solution. The reaction solution was stirred at room temperature for 4 hours, chloroform and water were added, and the mixture was stirred at room temperature. The organic layer was separated, washed with saturated brine, and dried over magnesium sulfate. After filtering the desiccant, the solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography (chloroform / methanol = 1: 4), and the desired N-{[6-bromo-3-methyl-2-oxo-4- (trifluoromethyl) -1,2, 3,4-Tetrahydroquinazolin-4-yl] methyl} -4-fluorobenzamide (4.0 mg, 53%) was obtained as a white solid.
¹ H-NMR (400 MHz, CD ₃ OD) δ: 3.88 (1H, d, J = 14.4 Hz), 4.43 (1H, d, J = 14.4 Hz), 6.80 (1H, d , J = 8.5 Hz), 7.08-7.15 (2H, m), 7.44 (1H, dd, J = 8.5, 2.1 Hz), 7.61 (1H, brs), 7 .65-7.71 (2H, m).

Reference example 1
[1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid 1- (tetrahydropyran-2-yl) -1H-pyrazole pyrazole (14.3 g, 0.21 mmol), A mixture of 3,4-dihydro-2H-pyran (29 mL, 0.32 mmol) and trifluoroacetic acid (0.1 mL, 0.0013 mmol) was heated to reflux for 5 hours. After cooling to room temperature, sodium hydride (60%, 0.2 g, 0.008 mmol) was added and stirred for 10 minutes. The reaction mixture was distilled under reduced pressure to obtain (60-65 ° C., 0.5-1 mmHg) 1- (tetrahydropyran-2-yl) -1H-pyrazole (30.8 g, 96%). N-Butyllithium (2.6 M hexane solution, 79 mL) was added at −78 ° C. to a stirred solution of the obtained 1- (tetrahydropyran-2-yl) -1H-pyrazole (30 g, 197 mmol) in THF (197 ml). The reaction solution was stirred at −78 ° C. for 30 minutes. To the reaction solution, boric acid triisopropyl ester (50.0 mL, 217 mmol) was added at −78 ° C. and stirred for 1 hour. 2N Hydrochloric acid (200 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 30 min. The solution was extracted 3 times with chloroform-ethanol. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the desired product (16.0 g, 41.4%) as a colorless solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.46-1.52 (2H, m), 1.54-1.66 (1H, m), 1.80 (1H, dq, J = 13.2, 2.9 Hz), 1.92-1.98 (1H, m), 2.21-2.31 (1H, m), 3.49-3.55 (1H, m), 3. 85-3.90 (1H, m), 5.92 (1H, dd, J = 10.2, 2.4 Hz), 6.72 (1H, d, J = 1.5 Hz), 7.50 (1H , D, J = 1.5 Hz).

Reference example 2
4-allyl-6-chloro-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one 1- (2-amino-5-chlorophenyl) -2,2, The title compound was obtained by a method according to Example 1 using 2-trifluoroethanone and allylmagnesium bromide as raw materials.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.99 (2H, m), 5.17-5.31 (2H, m), 5.53-5.64 (1H, m), 6.85 (1H, d, J = 8.8 Hz), 7.23 (1H, brs), 7.33 (1H, dd, J = 8.8, 2.2 Hz), 9.31 (1H, s)

Reference example 3
6-chloro-4- (3-hydroxypropyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one 4-allyl-6 obtained in Reference Example 2 -Chloro-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one (2.55 g, 8.74 mmol) was dissolved in THF (30 mL) and 9-BBN (0.5M-THF, 52 mL) was added dropwise to the reaction solution stirred at room temperature. The reaction solution was stirred overnight at room temperature, then ice-cooled, and 2N aqueous sodium hydroxide and 30% aqueous peroxide were added dropwise under ice-cooling. The reaction solution was stirred at room temperature for 30 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution, and then neutralized by adding a 10% aqueous citric acid solution to bring the reaction solution to pH = 4. The reaction solution was diluted with ethyl acetate and extracted. The organic layer was separated, washed with water and saturated brine, and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to give 6-chloro-4- (3-hydroxypropyl) -4- (trifluoromethyl) -1,4-dihydro-2H-3. , 1-Benzoxazin-2-one (2.56 g, 94.5%) was obtained as a colorless solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.17-1.28 (2H, m), 1.38-1.50 (2H, m), 3.40-3.43 (2H, m), 6.97 (1H, d, J = 8.8 Hz), 7.49 (1H, dd, J = 8.8, 2.0 Hz), 7.56 (1H, d, J = 2.0 Hz) ), 10.84 (1H, s).

Reference example 4
4- (2-Aminoethyl) -6-chloro-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one 1- (2-amino-5-chlorophenyl) The title compound was obtained by a method according to Example 27 using -2,2,2-trifluoroethanone and allylmagnesium bromide as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.09-2.17 (1H, m), 2.30-2.39 (1H, m), 2.51-2.57 (2H, m), 6.94 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 7.57 (1H, brs)

Reference Example 5
4- (2-aminopropyl) -6-chloro-4- (trifluoromethyl) -1,4-dihydro-2H-3,1-benzoxazin-2-one 1- (2-amino-5-chlorophenyl) The title compound was obtained by a method according to Example 27 using -2,2,2-trifluoroethanone and allylmagnesium bromide as raw materials.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.05-1.20 (1H, m), 1.27-1.41 (1H, m), 1.99-2.09 (1H, m), 2.42-2.56 (3H, m), 6.95 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 7.57 (1H, brs)

Reference Example 6
[3-Phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] boronic acid The title compound was obtained by a method according to Reference Example 1 using 3-phenylpyrazole as a starting material. It was.
¹ H-NMR (DMSO-d ₆ ) δ: 8.47 (1H, brs), 7.76 (2H, d, J = 7.8 Hz), 7.40 (2H, t, J = 7.8 Hz) , 7.29 (1H, t, J = 7.8 Hz), 7.10 (1H, s), 5.94 (1H, dd, J = 9.8, 2.4 Hz), 3.91 (1H, d, J = 11.2 Hz), 3.58-3.52 (1H, m), 2.40-2.30 (1H, m), 2.02-1.98 (1H, m), 1. 90-1.85 (1H, m), 1.68-1.50 (3H, m), 1.31-1.19 (1H, m).

  The compound according to the present invention has an excellent LCE inhibitory action and is useful as a therapeutic agent for various diseases associated with LCE, such as cardiovascular diseases, nervous system diseases, metabolic diseases, reproductive diseases, gastrointestinal diseases. It is.

Claims (11)

Formula (I)

[Where:
R ¹ represents C _1-6 alkyl substituted with halogen or C _3-8 cycloalkyl substituted with halogen ;
R ² is

Represents a group selected from the group consisting of:
W _{is, C 1-6 alkylene, C 2-6} represents _alkenylene, a _{C 2-6} alkynylene or _{C 3-6} cycloalkylene, said alkylene, alkenylene, alkynylene or cycloalkylene, optionally _{C 1} be substituted with halogen _-3 alkyl, optionally substituted with halogen, C _1-3 alkyloxy, hydroxyl or halogen optionally substituted,
R represents C _1-6 alkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, aryl or heteroaryl is halogen or halogen. optionally substituted _{C 1-6} alkyl, is optionally _{C 1-6} alkyloxy substituted with _{halogen, C 1-6} alkylsulfonyl, cyano, _{phenyl, C 1-6} alkylthio, hydroxyl, amino, _{C 1 -6} alkylamino, diC _1-6 alkylamino, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, diC _1-6 alkylaminoalkyl, C _{1 -6} alkoxy _{C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6} A · The _{carbamoyl, C 3-8 cycloalkylcarbamoyl,} may be substituted with _{C 1-6} alkylsulfonylamino or _{C 1-6} alkylaminosulfonyl,
R ³ represents a hydrogen atom, C _1-6 alkyl, aryl or heteroaryl,
X represents —O—, —C (R ^4a ) (R ^4b ) —, or —NR ⁵ —;
R ^4a , R ^4b and R ⁵ each independently represents hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein the C _1-6 alkyl, C _{3− 8} cycloalkyl, aryl or heteroaryl, halogen, C _1-6 alkyl optionally substituted by halogen, halogen optionally substituted C _1-6 alkyloxy, C _1-6 alkylsulfonyl, cyano, Optionally substituted with aryl or heteroaryl,
Y ₁ represents —CR ⁶ — or —N—,
Y ₂ represents —CR ⁷ — or —N—,
Y ₃ represents —CR ⁸ — or —N—,
Y ₄ represents -CR ⁹ -or -N-,
R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, hydroxyl, hydroxy C _{1- 6} alkyl, amino, C _1-6 alkylamino, diC _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, diC _1-6 alkylamino (C _{1- 6) alkyl, C 1-6} alkoxy _{C 1-6} alkyl, heterocyclyl, aryl, _{heteroaryl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6} alkylthio, arylsulfonyl, heteroarylsulfonyl, aryl sulfinyl, heteroaryl arylsulfinyl, arylthio, _{heteroarylthio, C 1-6} alkyl Carbonyl, arylcarbonyl, _{heteroarylcarbonyl, C 1-6} alkylcarbonylamino, arylcarbonylamino, _{heteroarylcarbonylamino, C 1-6 alkylcarbamoyl, C 3-8} cycloalkylcarbamoyl, heterocyclylthio carbamoyl, arylcarbamoyl, hetero arylcarbamoyl C _1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, C _1-6 alkylsulfamoyl, arylsulfamoyl or heteroarylsulfamoyl, wherein said alkyl, cycloalkyl, heterocyclyl , aryl or heteroaryl, halogen, optionally substituted by halogen C _1-6 alkyl, a C _1-6 a optionally substituted by halogen Kiruokishi, C _1-6 alkylsulfonyl, carboxyl and salts thereof that are acceptable compound represented by or a pharmaceutically In may also be 'substituted with from consisting radical selected from the group cyano. Formula (I-1)

[Wherein R ¹ , R ² , R ³ , Y ₁ , Y ₂ , Y ₃ , Y ₄ and X are as defined in claim 1] or a pharmaceutically acceptable salt thereof . The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ is trifluoromethyl. The compound or pharmaceutically acceptable compound according to any one of claims 1 to 3, wherein R ² is represented by formula (II-1), formula (II-4), or formula (II-6). Its salt. R in R ² is a phenyl or heteroaryl, wherein the substituents are halogen, cyano, halogen substituted C _1-6 alkyl, C _1-6 alkyl optionally substituted by halogen Oxy, C _1-6 alkylsulfonyl, C _1-6 alkylthio, hydroxyl, amino, C _1-6 alkylamino, diC _1-6 alkylamino, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _{1 -6} alkylamino C _1-6 alkyl, diC _1-6 alkylamino C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkylcarbonylamino, C _{1-6 alkylcarbamoyl, C 3-8 cycloalkylcarbamoyl, C 1-6} alkylsulfonylamino and _{C 1-6} A May be substituted with a substituent selected from the group consisting kill sulfamoyl compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom. When Y ₁ , Y ₂ , Y ₃ and Y ₄ are respectively —CR ⁶ —, —CR ⁷ —, —CR ⁸ — and —CR ⁹ —, among R ⁶ , R ⁷ , R ⁸ and R ⁹ , At least one of which is halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, hydroxyl, hydroxy C _1-6 alkyl, amino, C _1-6 alkylamino, diC _{1 -6} alkylamino, amino C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, diC _1-6 alkylaminoalkyl, C _1-6 alkoxy C _1-6 alkyl, heterocyclyl, aryl, heteroaryl , _{C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6} alkylthio, arylsulfonyl, heteroarylsulfonyl, Arirusuru Iniru, heteroaryl arylsulfinyl, arylthio, _{heteroarylthio, C 1-6} alkylcarbonyl, arylcarbonyl, _{heteroarylcarbonyl, C 1-6} alkylcarbonylamino, arylcarbonylamino, _{heteroarylcarbonylamino, C 1-6} alkylcarbamoyl, C _3-8 cycloalkylcarbamoyl, heterocyclylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, C _1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, C _1-6 alkylsulfamoyl, arylsulfamoyl and hetero Selected from the group consisting of arylsulfamoyl, wherein said aryl or heteroaryl is substituted with halogen, halogen; Which may be C _1-6 alkyl, halogen optionally substituted C _1-6 alkyloxy, C _1-6 alkylsulfonyl, may be substituted with a group selected from carboxyl and the group consisting of cyano And the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the remainder is a hydrogen atom. X is, -O- or -NR 5 ^- is a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7. A long-chain fatty acid elongation enzyme (LCE) inhibitor comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. Metabolic syndrome, fatty liver, hyperlipidemia, dyslipidemia, non-alcoholic fat containing the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof as an active ingredient Treatment for liver, obesity, diabetes, bulimia, malignant neoplasm or infectious disease.